Редактирование: CCL2 (раздел)

==Publications==

{{medline-entry
|title=Assessment of neuroinflammation in the aging hippocampus using large-molecule microdialysis: Sex differences and role of purinergic receptors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33166661
|abstract=Aging is associated with an enhanced neuroinflammatory response to acute immune challenge, often termed "inflammaging." However, there are conflicting reports about whether baseline levels of inflammatory markers are elevated under ambient conditions in the aging brain, or whether such changes are observed predominantly in response to acute challenge. The present studies utilized two distinct approaches to assess inflammatory markers in young and aging Fischer 344 rats. Experiment 1 examined total tissue content of inflammatory markers from hippocampus of adult (3 month), middle-aged (12 month), and aging (18 month) male Fischer (F) 344 rats using multiplex analysis (23-plex). Though trends emerged for several cytokines, no significant differences in basal tissue content were observed across the 3 ages examined. Experiment 2 measured extracellular concentrations of inflammatory factors in the hippocampus from adult (3 month) and aging (18 month) males and females using large-molecule in vivo microdialysis. Although few significant aging-related changes were observed, robust sex differences were observed in extracellular concentrations of [[CCL3]], [[[[CCL2]]0]], and IL-1α. Experiment 2 also evaluated the involvement of the P2X7 purinergic receptor in neuroinflammation using reverse dialysis of the selective agonist BzATP. BzATP produced an increase in IL-1α and IL-1β release and rapidly suppressed the release of [[CXCL1]], [[CCL2]], [[CCL3]], [[[[CCL2]]0]], and IL-6. Other noteworthy sex by aging trends were observed in [[CCL3]], IL-1β, and IL-6. Together, these findings provide important new insight into late-aging and sex differences in neuroinflammation, and their regulation by the P2X7 receptor.

|keywords=* Aging
* Hippocampus
* Large-molecule microdialysis
* Neuroinflammation
* Purinergic receptors
|full-text-url=https://sci-hub.do/10.1016/j.bbi.2020.11.013
}}
{{medline-entry
|title=Metformin alters peripheral blood mononuclear cells (PBMC) senescence biomarkers gene expression in type 2 diabetic patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33187870
|abstract=Although there is increasing evidence showing that cell senescence is increased in circulating PBMC in type 2 diabetes mellitus (T2DM), the data are contradictory. This study examined several senescence biomarkers, including [[LMNA]]/C transcript variants, p16 , p53, and p21 , in PBMC of T2DM patients and the effect of Metformin on these senescence markers. Blood samples were obtained from 30 lean, 30 obese, 20 newly diagnosed type 2 diabetes mellitus (T2DM), and 30 T2DM on Metformin. PBMC were isolated and mRNA expression of the senescence biomarkers were quantified by RT-qPCR. The effect of ectopic expression of [[LMNA]] and LMNC in human monocytic cells lines (THP-1 and U937) on several inflammatory mediators were also examined. [[LMNA]] expression was significantly higher in PBMC of obese and T2DM patients. LMNC expression was significantly inhibited in T2DM patients. [[LMNA]]Δ10 and Progerin mRNA expression was not detected in PBMC of all groups. Expression of p16 , p21  and p53 were inhibited significantly in T2DM. Metformin treatment reverted [[LMNA]], LMNC, and p53 expression levels to normal levels. Upregulation of [[LMNA]] in monocytic THP-1 and U937 cell lines induced [[CD68]], TNFα, [[CCL2]], IL-6 and [[NOS2]]. These data support the notion that [[LMNA]] may mediate senescence in PBMCs of T2DM by upregulating inflammatory pathways. Metformin may exert its anti-inflammatory property by modulation of senescence mediator [[LMNA]].

|keywords=* Inflammation and cellular senescence
* Insulin resistance
* LMNA/C transcript variants
* Mononuclear cells
* Type 2 diabetes mellitus
|full-text-url=https://sci-hub.do/10.1016/j.jdiacomp.2020.107758
}}
{{medline-entry
|title=[[IL1B]] triggers inflammatory cytokine production in bovine oviduct epithelial cells and induces neutrophil accumulation via [[CCL2]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33099841
|abstract=The oviduct is essential for reproduction. We previously showed that oviduct epithelial cells (OECs) isolated from aged cows expressed higher levels of inflammatory cytokines, including interleukin (IL) 1A and [[IL1B]]. In addition, aging is associated with tissue dysfunction and cellular senescence via a senescence-associated secretory phenotype (SASP) and immune cell accumulation. We investigated whether [[IL1A]] or [[IL1B]] causes SASP production, cellular senescence, and inflammatory responses in bovine OECs. The OECs were isolated from bovine oviducts from young (mean 50.3 months) and aged cows (mean 157.0 months) and cultured. Treatment with [[IL1A]] or [[IL1B]] induced SASP production (IL8, [[IL6]], TNFA, and [[CCL2]]) and mRNA expression of cell adhesion molecules in bovine OECs, but both IL1s did not induce cellular senescence in OECs and migration of polymorphonuclear neutrophils (PMNs). Cultured medium of OECs treated with IL1s, especially [[IL1B]], dramatically induced PMN migration. Treatment with the [[CCL2]] inhibitor, but not IL8 or its receptor [[CXCR2]] inhibitors, significantly reduced immune cell migration in [[IL1B]]-treated OEC-cultured medium. Treatment with [[IL1B]] increased PMN adhesion to OECs, resulting in further SASP production in OECs due to a PMN-OEC interaction. We suggest that senescence-associated IL1s cause SASP production in bovine OECs and [[CCL2]] induced by [[IL1B]] is essential for the migration of immune cells to OECs. Specifically, [[IL1B]] regulates PMN migration and adhesion to bovine OECs, and PMNs accelerate inflammatory cytokine production from bovine OECs via a direct interaction. These phenomena may contribute to chronic oviductal inflammation, resulting in subfertility.

|keywords=* CCL2
* cellular senescence
* inflammaging
* senescence-associated secretory phenotype
|full-text-url=https://sci-hub.do/10.1111/aji.13365
}}
{{medline-entry
|title=Eosinophils and White Fat: Protection from Worms and Inflammaging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32718231
|abstract=Proinflammatory alterations of white adipose tissue (WAT) with increasing age play an important role in mammalian aging. WAT produced eotaxin-1 (CCL11-C-C motif chemokine ligand 11) and monocyte chemoattractant protein 1 (MCP-1) ([[CCL2]]) are elevated in old mammals. Obese and old adipose tissues produce excessive proinflammatory cytokines such as interleukin (IL)-6, [[CCL2]], and IL-1-beta that contribute to inflammaging. WAT-based inflammaging involves an altered homeostatic equilibrium between proinflammatory cells such as activated type 1 macrophages, B cells (high IgJ) and T cells, and anti-inflammatory eosinophils and Tregs. Specifically, young and lean individuals exhibit a high eosinophil-to-macrophage ratio with an enrichment of alternative activated tissue macrophages that is reduced in the WAT of aging mice. Eosinophils from young animals adoptively transferred to old mice, home to WAT and reverse many of the immunoinflammatory signatures associated with aging. Whether eosinophil-based therapies for inflammaging could be created remains an open question.

|keywords=* aging
* eosinophils
* inflammaging
* innate immune system
* white adipose tissue
|full-text-url=https://sci-hub.do/10.1089/rej.2020.2375
}}
{{medline-entry
|title=[[CXCL9]] and [[CXCL10]] display an age-dependent profile in Chagas patients: a cohort study of aging in Bambui, Brazil.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32393333
|abstract=Chagas disease is endemic in Latin America and still represents an important public health problem in the region. Chronic cardiomyopathy is the most significant chronic form due to its association with morbidity and mortality. The last decade has seen increasing evidence that inflammatory cytokines and chemokines are responsible for the generation of inflammatory infiltrate and tissue damage, with chronic chagasic cardiomyopathy patients presenting a pro-inflammatory immune response. Although studies have evaluated the role of chemokines in experimental T. cruzi infection, few have addressed their systemic profile, especially for human infection and in aging populations. The present work aimed to use the data from a large population based study of older adults, conducted in an endemic area for Chagas disease, to examine the association between serum levels of cytokines and chemokines, T. cruzi infection and electrocardiogram (ECG) abnormality. The present work evaluated serum levels of [[CCL2]], [[CXCL9]], [[CXCL10]], [[CCL5]], [[CXCL8]], IL-1β, IL-6, [[TNF]], IL-12 and IL-10 by Flow Cytometric Bead Array assay (CBA) and the results expressed in pg/ml. The baseline survey started in January 1st 1997, with 1284 participants of an aged population-based cohort. Participants signed an informed consent at baseline and at each subsequent visit and authorized death certificate and medical records verification. Our results demonstrated that Chagas disease patients had higher serum levels of [[CXCL9]], [[CXCL10]] and IL-1β and lower serum levels of [[CCL5]] than non-infected subjects. Moreover, our data demonstrated that [[CXCL9]] and [[CXCL10]] increased in an age-dependent profile in Chagas disease patients. Together, this study provided evidences that serum biomarkers increase along the age continuum and may have potential implications for establishing clinical management protocols and therapeutic intervention in Chagas disease patients.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Brazil
* Chagas Disease
* Chemokine CXCL10
* Chemokine CXCL9
* Cohort Studies
* Electrocardiography
* Female
* Humans
* Male
* Middle Aged
* Trypanosoma cruzi
|keywords=* Chagas disease
* Chemokines
* Cohort
* Cytokines
* Immune biomarkers
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216412
}}
{{medline-entry
|title=p53 and p53-related mediators PAI-1 and IGFBP-3 are downregulated in peripheral blood mononuclear cells of HIV-patients exposed to non-nucleoside reverse transcriptase inhibitors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32272174
|abstract=The improved effectiveness and safety of the combined antiretroviral therapy (cART) has largely diminished mortality and AIDS-defining morbidity of HIV-patients. Nevertheless, chronic age-related diseases in these individuals are more common and their underlying pathogenic mechanisms of these actions seem to involve accelerated aging and enhanced inflammation. The present study explores markers of these processes in a heterogenous Spanish HIV cohort using peripheral blood samples of HIV-patients and matched uninfected controls. We isolated periheral blood mononuclear cells (PBMCs) and i) compared the expression of a panel of 14 genes related to inflammation and senescence in PBMCs of HIV-patients vs matched uninfected controls, ii) analyzed the expression in HIV-patients in association with a number of demographic, biochemical and immunological parameters and iii) in relation with the current cART they received. PBMCs of HIV-patients displayed significantly increased expression of general inflammatory genes ([[IL6]], [[IL18]] and [[CXCL10]]) and this occurs irrespectively of the antiviral therapy they have been receiving. Conversely, levels of senescence-associated genes [[TP53]], [[SERPINE1]]andIGFBP3 were slightly but significantly reduced in patients compared to uninfected matched individuals and this effect is related to NNRTI-containing treatments. The expression of the inflammatory markers [[IL6]], [[IL18]], [[IL1B]], TNFA, [[RELA]], [[CCL2]], [[[[CCL2]]0]] and [[CXCL10]] displayed correlation with certain demographic, morbidity- and HIV infection-related parameters. The levels of [[TP53]] mRNA were positively associated only with plasma LDL. Correlation analysis between the expressions of pairs of genes revealed a different pattern between HIV-patients and controls. The diminished expression of [[TP53]] and [[SERPINE1]] in HIV-patients was also observed at a protein level, and the correlation between the two proteins (p53 and PAI1) in patients and controls showed the opposite trend. In conclusion, HIV-patients show dysregulation of p53 and p53-related mediators, a phenomenon which may be of pathophysiological relevance and could be related to the shorter health- and/or life-span observed in these individuals.

|keywords=* Aging
* Antiretroviral drugs
* HIV
* Inflammation
* NNRTI
* Senescence
* p53
|full-text-url=https://sci-hub.do/10.1016/j.antiviral.2020.104784
}}
{{medline-entry
|title=β1 Integrin regulates adult lung alveolar epithelial cell inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31873073
|abstract=Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of β1 integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged β1 integrin-deficient mice exhibited chronic obstructive pulmonary disease-like (COPD-like) pathology characterized by emphysema, lymphoid aggregates, and increased macrophage infiltration. These histopathological abnormalities were preceded by β1 integrin-deficient AEC dysfunction such as excessive ROS production and upregulation of NF-κB-dependent chemokines, including [[CCL2]]. Genetic deletion of the [[CCL2]] receptor, Ccr2, in mice with β1 integrin-deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for β1 integrin in alveolar homeostasis in the adult lung.
|mesh-terms=* Aging
* Alveolar Epithelial Cells
* Animals
* Cell Adhesion
* Chemokine CCL2
* Chemokines
* Disease Models, Animal
* Epithelium
* Integrin beta1
* Lung
* Macrophages
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Pneumonia
* Pulmonary Disease, Chronic Obstructive
* Receptors, CCR2
|keywords=* COPD
* Inflammation
* Integrins
* Macrophages
* Pulmonology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098727
}}
{{medline-entry
|title=Arsenic induces human chondrocyte senescence and accelerates rat articular cartilage aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31734849
|abstract=Arsenic-contaminated drinking water is known to be a serious human health problem. A previous epidemiological study has indicated that arsenic levels in blood were higher in arthritis patients compared to age-matched control subjects. Bone is known as an important arsenic store compartment in the body. Arsenic exposure has been suggested to promote senescence in human mesenchymal stem cells that may affect the balance of adipogenic and osteogenic differentiation. The toxicological effect and mechanism of arsenic exposure on articular chondrocytes still remain unclear. Here, we investigated the arsenic-induced senescence in cultured human articular chondrocytes and long-term arsenic-exposed rat articular cartilage. Arsenic trioxide (As O ; 1-5 μM) significantly induced senescence in human articular chondrocytes by increasing senescence-associated β-galactosidase (SA-β-Gal) activity and protein expression of p16, p53, and p21. Arsenic induced the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) proteins. The inhibitors of p38 and JNK significantly reversed the arsenic-induced chondrocyte senescence. Arsenic could also trigger the induction of [[GATA4]]-NF-κB signaling and senescence-associated secretory phenotype (SASP) by increasing IL-1α, IL-1β, TGF-β, [[TNF]]-α, [[CCL2]], PAI-1, and [[MMP13]] mRNA expression. The increased cartilage senescence and abrasion were also observed in a rat model long-term treatment with arsenic (0.05 and 0.5 ppm) in drinking water for 36 weeks as compared to age-matched control rats. The phosphorylation of p38 and JNK and the induction of [[GATA4]]-NF-κB signaling and SASP were enhanced in the rat cartilages. Taken together, these findings suggest that arsenic exposure is capable of inducing chondrocyte senescence and accelerating rat articular cartilage aging and abrasion.

|keywords=* Aging
* Arsenic
* Articular cartilage
* Human chondrocyte
* Senescence
* Senescence-associated secretory phenotype
|full-text-url=https://sci-hub.do/10.1007/s00204-019-02607-2
}}
{{medline-entry
|title=Klotho-mediated targeting of [[CCL2]] suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31545552
|abstract=Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including [[CCL2]], which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of [[CCL2]] by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, [[CCL2]] was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific [[CCR2]] antagonist. We further show that Klotho can suppress NF-κB activation during DOX-induced senescence and thus block [[CCL2]] transcription. Low expression of Klotho, or high expression of [[CCL2]] in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including [[CCL2]]. The identification of key SASP factors such as [[CCL2]] may provide potential therapeutic targets for improving CRC therapy.
|mesh-terms=* Aged
* Cell Line, Tumor
* Cell Movement
* Cell Proliferation
* Cellular Microenvironment
* Cellular Senescence
* Chemokine CCL2
* Colorectal Neoplasms
* Disease Progression
* Down-Regulation
* Doxorubicin
* Female
* Glucuronidase
* Human Umbilical Vein Endothelial Cells
* Humans
* Male
* Middle Aged
* NF-kappa B
* Neoplasm Invasiveness
* Proportional Hazards Models
* Signal Transduction
* Stromal Cells
|keywords=* CCL2
* Klotho
* colorectal cancer
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822285
}}
{{medline-entry
|title=Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30872008
|abstract=Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra Terminal Domain (BET) proteins are essential to inflammatory gene transcription. BET proteins (BRD2, [[BRD3]], [[BRD4]], and BRDT) have varied effects including chromatin remodeling, histone acetyltransferase activity, and as scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription. BRD2/4 are of particularly interest to stroke-induced neuroinflammation that contributes to delayed cell death as they are required for NF-κB-dependent gene transcription. We hypothesized that targeting BET proteins for degradation with dBET1, a proteolysis targeting chimera (PROTAC) that combines the highly selective BET inhibitor JQ1 and a ligand for cereblon E3 ubiquitin ligase, will reduce brain injury in ischemic stroke. Male aged mice (18-20 months old) were subjected to permanent occlusion of the middle cerebral artery and received either vehicle or dBET1 (10 mg/kg; i.p.) at various times after stroke. Neurobehavioral tests were performed before (baseline) and at 24 and 48 h after stroke induction. Infarct volume was quantified at 48 h. Data showed that BET degradation significantly reduced infarct volume in permanent focal cerebral ischemia in aged mice, and this was associated with reduced brain levels of pro-inflammatory mediators including [[TNF]]-α, [[CXCL1]], [[[[CXCL1]]0]], [[CCL2]], and matrix metalloproteinase-9. Treatment with dBET1 significantly reduced blood-brain barrier damage and infiltration of neutrophils into the ischemic brain. Importantly, treatment with the BET degrader dBET1 resulted in a significant improvement in stroke-induced neurological deficits. Collectively, these data indicate that BET proteins are a novel target for neuroprotection in ischemic stroke.
|mesh-terms=* Aging
* Animals
* Brain Injuries
* Brain Ischemia
* Disease Models, Animal
* Male
* Mice, Inbred C57BL
* Nerve Tissue Proteins
* Neuroprotective Agents
* Protein Transport
* Receptors, Cell Surface
* Stroke
* Transcription Factors
|keywords=* Aged mice
* BET proteins
* BRD4
* Ischemic stroke
* Neuroinflammation
* dBET1
|full-text-url=https://sci-hub.do/10.1016/j.neuint.2019.03.004
}}
{{medline-entry
|title=Membrane metallo-endopeptidase mediates cellular senescence induced by oncogenic [[PIK3CA]]  accompanied with pro-tumorigenic secretome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30671946
|abstract=The hotspot mutation H1047R in the oncogenic [[PIK3CA]] gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade. Aberrant elevated PI3K activation has been reported to promote the tumorigenesis of breast cancer, but the mechanisms underlying are still needed to be elucidated. Here, we found that continuously activating [[PIK3CA]]  conferred human mammary epithelial MCF-10A cells to cellular senescence upon serum-starvation. Similarly, breast cancer T47D and HCC1954 cells harboring H1047R mutation were senescent when cells were deprived of serum. PI3K/AKT/mTOR axis but not p53 or RB might be required for the induction of senescence. Notably, membrane metallo-endopeptidase ([[MME]]) was identified as a downstream effector of PI3K to mediate the induction of senescence, which might be associated with its glycosylation. Senescent cells elicited a distinct secretome dependent on PI3K and [[MME]]. Specifically, IL-6 promoted the proliferation of normal cells and [[CCL2]] induced the M2-like polarization of macrophages, which might create an immunosuppressive microenvironment during the initiation and/or development of breast cancer. This study shed new light on the tumorigenesis induced by hyper-activated PI3K and might provide new clues for the prevention and therapy of breast cancer.
|mesh-terms=* Animals
* Breast Neoplasms
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Chemokine CCL2
* Class I Phosphatidylinositol 3-Kinases
* Epithelial Cells
* Glycosylation
* Humans
* Interleukin-6
* Mammary Glands, Human
* Metalloendopeptidases
* Mice
* Mice, Inbred BALB C
* Proto-Oncogene Proteins c-akt
* TOR Serine-Threonine Kinases
* Tumor Suppressor Protein p53
|keywords=* PI3Kα
* breast cancer
* macrophage
* membrane metallo-endopeptidase
* senescence
|full-text-url=https://sci-hub.do/10.1002/ijc.32153
}}
{{medline-entry
|title=Isoflurane anesthesia impairs the expression of immune neuromodulators in the hippocampus of aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30571762
|abstract=Cognitive dysfunction is one of the most common postoperative complications experienced by older patients after anesthesia and surgery but the cause remains unknown. Immune molecules are essential for many aspects of neural homeostasis, including learning and memory, and an imbalance in immune neuromodulators is implicated in the development of neural dysfunction. Aging alters the control of neuroinflammatory cascades and general anesthetics are immunosuppressants. Therefore, we hypothesized that general anesthesia disturbs neuroimmune signaling in an age-dependent fashion. We tested this hypothesis by examining gene expression of key immune neuromodulators including IL-1β, TNFα, and [[CCL2]] in the hippocampus of young adult (3 mo) and aged (20 mo) mice following isoflurane anesthesia. We show that isoflurane anesthesia increases expression of these signaling molecules in the hippocampus of young adult mice but decreases it in the hippocampus of old mice. Furthermore, anesthetized old mice had an amplified hippocampal neuroimmune response to systemically administered lipopolysaccharide compared to age-matched carrier controls. Together, these data indicate that isoflurane anesthesia disrupts hippocampal neuroimmune mediator gene expression in the old brain and suggests a potential mechanism by which general anesthesia can contribute to disordered neuronal homeostasis and post-anesthesia cognitive disability in older subjects.
|mesh-terms=* Aged
* Aging
* Anesthetics, Inhalation
* Animals
* Chemokine CCL2
* Cognitive Dysfunction
* Gene Expression
* Hippocampus
* Humans
* Immunologic Factors
* Interleukin-10
* Interleukin-1beta
* Isoflurane
* Lipopolysaccharides
* Male
* Mice
* Mice, Inbred C57BL
* Models, Animal
* Neurotransmitter Agents
* Postoperative Complications
* Tumor Necrosis Factor-alpha

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301699
}}
{{medline-entry
|title=Melatonin and inflammation-Story of a double-edged blade.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30242884
|abstract=Melatonin is an immune modulator that displays both pro- and anti-inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte-derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti-inflammatory actions are of particular medicinal interest, because they are observed in high-grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low-grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti-inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase-2, inhibition of high-mobility group box-1 signaling and toll-like receptor-4 activation, prevention of inflammasome [[NLRP3]] activation, inhibition of NF-κB activation and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti-inflammatory cytokines. Proinflammatory actions of amyloid-β peptides are reduced by enhancing α-secretase and inhibition of β- and γ-secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin-1 ([[SIRT1]]), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA-[[CCL2]]. The conclusion on a partial mediation by [[SIRT1]] is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown.
|mesh-terms=* Animals
* Humans
* Inflammation
* Melatonin
* NF-E2-Related Factor 2
* Signal Transduction
* Sirtuin 1
|keywords=* SIRT1
* aging
* circadian
* cytokines
* immune system
* inflammaging
* melatonin
|full-text-url=https://sci-hub.do/10.1111/jpi.12525
}}
{{medline-entry
|title=Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30025494
|abstract=Macroautophagy/autophagy is considered as an evolutionarily conserved cellular catabolic process. In this study, we aimed to elucidate the role of autophagy in vascular smooth muscle cells (SMCs) on atherosclerosis. SMCs cultured from mice with SMC-specific deletion of the essential autophagy gene atg7 (Atg7cKO) showed reduced serum-induced cell growth, increased cell death, and decreased cell proliferation rate. Furthermore, 7-ketocholestrerol enhanced apoptosis and the expression of [[CCL2]] (chemokine [C-C motif] ligand 2) with the activation of TRP53, the mouse ortholog of human and rat [[TP53]], in SMCs from Atg7cKO mice. In addition, Atg7cKO mice crossed with Apoe (apolipoprotein E)-deficient mice (apoeKO; Atg7cKO:apoeKO) showed reduced medial cellularity and increased TUNEL-positive cells in the descending aorta at 10 weeks of age. Intriguingly, Atg7cKO: apoeKO mice fed a Western diet containing 1.25% cholesterol for 14 weeks showed a reduced survival rate. Autopsy of the mice demonstrated the presence of aortic rupture. Analysis of the descending aorta in Atg7cKO:apoeKO mice showed increased plaque area, increased TUNEL-positive area, decreased SMC-positive area, accumulation of macrophages in the media, and adventitia and perivascular tissue, increased [[CCL2]] expression in SMCs in the vascular wall, medial disruption, and aneurysm formation. In conclusion, our data suggest that defective autophagy in SMCs enhances atherosclerotic changes with outward arterial remodeling.
|mesh-terms=* Animals
* Aorta
* Apolipoproteins E
* Atherosclerosis
* Autophagy
* Autophagy-Related Protein 7
* Cell Death
* Cells, Cultured
* Disease Models, Animal
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Muscle, Smooth, Vascular
* Plaque, Atherosclerotic
* Vascular Remodeling
|keywords=* Aneurysm
* atherosclerosis
* autophagy
* cell death
* senescence
* smooth muscle cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152523
}}
{{medline-entry
|title=Urine Cytokine and Chemokine Levels Predict Urinary Tract Infection Severity Independent of Uropathogen, Urine Bacterial Burden, Host Genetics, and Host Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29891542
|abstract=Urinary tract infections (UTIs) are among the most common infections worldwide. Diagnosing UTIs in older adults poses a significant challenge as asymptomatic colonization is common. Identification of a noninvasive profile that predicts likelihood of progressing from urine colonization to severe disease would provide a significant advantage in clinical practice. We monitored colonization susceptibility, disease severity, and immune response to two uropathogens in two mouse strains across three age groups to identify predictors of infection outcome. [i]Proteus mirabilis[/i] caused more severe disease than [i]Escherichia coli[/i], regardless of mouse strain or age, and was associated with differences in interleukin-1β (IL-1β), beta interferon (IFN-β), [[CXCL5]] (LIX), [[CCL5]] (RANTES), and [[CCL2]] (MCP-1). In a comparison of responses to infection across age groups, mature adult mice were better able to control colonization and prevent progression to kidney colonization and bacteremia than young or aged mice, regardless of mouse strain or bacterial species, and this was associated with differences in IL-23, [[CXCL1]], and [[CCL5]]. A bimodal distribution was noted for urine colonization, which was strongly associated with bladder CFU counts and the magnitude of the immune response but independent of age or disease severity. To determine the value of urine cytokine and chemokine levels for predicting severe disease, all infection data sets were combined and subjected to a series of logistic regressions. A multivariate model incorporating IL-1β, [[CXCL1]], and [[CCL2]] had strong predictive value for identifying mice that did not develop kidney colonization or bacteremia, regardless of mouse genetic background, age, infecting bacterial species, or urine bacterial burden. In conclusion, urine cytokine profiles could potentially serve as a noninvasive decision support tool in clinical practice and contribute to antimicrobial stewardship.
|mesh-terms=* Animals
* Bacteremia
* Biomarkers
* Chemokines
* Colony Count, Microbial
* Cytokines
* Disease Models, Animal
* Escherichia coli
* Escherichia coli Infections
* Kidney
* Mice
* Mice, Inbred C57BL
* Mice, Inbred CBA
* Predictive Value of Tests
* Proteus Infections
* Proteus mirabilis
* Severity of Illness Index
* Urinary Tract Infections
|keywords=* CAUTI
* Escherichia coli
* Proteus mirabilis
* UTI
* aging
* bacteremia
* chemokine
* cytokine
* pyelonephritis
* urinary tract infection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105902
}}
{{medline-entry
|title=Infiltrating macrophages contribute to age-related neuroinflammation in C57/BL6 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29758231
|abstract=The recognized role of neuroinflammation in the age-related deterioration of neuronal function highlights the importance of understanding the factors that control microglial activation. Microglia, as the immune cells of the brain, are the arbiters of the inflammatory profile in the brain. Normally they are maintained in a quiescent state by means of ligand-receptor interactions with neurons, within a prevailing anti-inflammatory microenvironment. The evidence indicates that, as the ageing process continues, microglia become activated, shift towards an inflammatory phenotype and alter the milieu in the brain. Although there has been progress in identifying factors that contribute to age-related microglial activation, our understanding remains incomplete. Here we report that there was an age-related increase in circulating inflammatory cytokines, accompanied by microglial activation. Neutrophils, and to a greater extent, macrophages, infiltrate the brain with age, perhaps as a result of increased chemokine expression in the brain, specifically [[CXCL1]] and [[CCL2]]. We sought to determine whether macrophages might trigger microglial activation and the evidence shows that conditioned medium obtained from interferon-γ (IFNγ)-stimulated macrophages potently activated microglia. The data suggest that infiltrating macrophages may be one factor that contributes to age-related microglial activation.
|mesh-terms=* Aging
* Animals
* Brain Diseases
* Chemokine CCL2
* Chemokine CXCL1
* Inflammation
* Interferon-gamma
* Macrophages
* Mice
* Microglia
|keywords=* Age
* Inflammatory cytokines
* Macrophage infiltration
* Microglial activation
|full-text-url=https://sci-hub.do/10.1016/j.mad.2018.05.003
}}
{{medline-entry
|title=Time-Dependent Changes in Local and Serum Levels of Inflammatory Cytokines as Markers for Incised Wound Aging of Skeletal Muscles.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29760352
|abstract=Wound age estimation is an important research field in forensic pathology. The expression levels of cytokines in the incised skeletal muscle were analyzed using a mouse model to explore the applicability for wound aging. A 5-mm long incisional wound was made at the biceps femoris muscle, and the muscle and serum were sampled at 6, 12, 24 and 48 hours after injury. Using a multiplex bead-based immunoassay, we measured the tissue levels of nine cytokines (IL-1β, IL-6, IL-7, [[CCL2]], [[CCL3]], [[CCL4]], [[CXCL1]], [[CXCL2]], and [[CXCL1]]0), which are all involved in the pathways of inflammatory response and tissue injury. Immunoassay of post-injury muscle samples revealed significant increases in the levels of six cytokines, except for [[CCL3]], [[CCL4]] and IL-7, at 6 hours after injury. The elevated tissue levels of these six cytokines were maintained during 48 hours after injury, although the levels of IL-6 and [[CXCL1]] were significantly decreased at 12 hours. In case of [[CCL3]], its tissue levels were increased only at 12 hours. By contrast, [[CCL4]] and IL-7 levels were increased only at 48 hours. Moreover, serum levels of most cytokines, except for [[CXCL1]], remained unchanged during 24 hours after injury, followed by significant increases at 48 hours. Serum [[CXCL1]] levels were increased at 6 hours and then decreased to the basal levels. Thus, the significant increase in the muscle levels of [[CXCL1]] and IL-7 was observed at 6 and 48 hours after injury, respectively. Measuring muscle [[CXCL1]] and IL-7 levels is helpful for estimating incised wound aging.
|mesh-terms=* Aging
* Animals
* Biomarkers
* Cytokines
* Gene Expression Regulation
* Immunoassay
* Inflammation Mediators
* Male
* Mice, Inbred BALB C
* Muscle, Skeletal
* RNA, Messenger
* Time Factors
* Wounds and Injuries
|keywords=* bead-based immunoassay
* cytokines
* sharp force injury
* skeletal muscle
* wound aging
|full-text-url=https://sci-hub.do/10.1620/tjem.245.29
}}
{{medline-entry
|title=Age-related pro-inflammatory and pro-angiogenic changes in human aqueous humor.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29487806
|abstract=To reveal age-related aqueous cytokine changes in human aqueous humor. Aqueous humor was collected from 12 young children (3-6.5 years old) and 71 healthy adults (22-106 years old) with cataract but without other systemic or ocular disorders. Levels of 22 cytokines, chemokines and vascular endothelial growth factor (VEGF) were measured and analyzed. The following proteins showed significant increase from childhood to adult: interferon-gamma (IFN-γ), interleukin (IL)-13, IL-6, IL-12(p70), IL-10, [[CCL2]], [[CCL3]], [[CCL4]], [[CXCL8]], [[CXCL9]], [[CXCL10]], IFN-α2 and VEGF (all [i]P[/i]<0.05). IFN-γ, IL-13, IL-12(p70), IL-10, [[CCL3]], [[CXCL9]] and VEGF also showed moderate strength age-related increase in the adult group ([i]r[/i]>0.5). The strength of correlation between aging and [[CCL4]] were fair ([i]r[/i]=0.398). The concentrations of IL-2, IL-4, IL-5, IL-1β and [[TNF]]-α were low in both groups. From childhood to adult, the immunological milieu of the anterior chamber become more pro-inflammatory and pro-angiogenic. Such changes may represent the parainflammation state of the human eye.

|keywords=* aging
* aqueous humor
* cytokines
* macrophage
* parainflammation
* vascular endothelial growth factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824071
}}
{{medline-entry
|title=Immune senescence and biomarkers profile of Bambuí aged population-based cohort.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29247791
|abstract=During immunosenescence many proinflammatory markers such as cytokines and chemokines are increased. This process called by Franceschi and colleagues as inflammaging is associated with chronic inflammation and the ethiology and pathophysiolgy of many ageing diseases as Alzheimer's and atherosclerosis. The knowledge of immune profile during ageing may provide some interventions that would improve the immune function in elderly and quality of life for old people. However, the identification of a group of potential biomarkers to monitor the ageing process is very difficult. In addition, most of the evidence evaluating immune biomarkers profile is based on data from older Caucasian adults. To our knowledge, no previous Latin American old population-based cohort has evaluated immunological parameters along the ageing process. The present work evaluated [[CXCL8]], [[CXCL9]], [[CXCL10]], [[CCL2]], [[CCL5]], IL-1, IL-6, IL-12, [[TNF]] and IL-10 serum levels in 1494 older adults aged 60 to 95 from a population based ageing cohort in Brazil. Our data suggest that there is an increased positive predicted probability of participants to be a high producer of IL-6, [[CXCL8]] and [[CXCL9]]. Moreover, results did not differ between men and women, except for [[CXCL10]] that increased only in men. Results were not different in the adjusted model by many potential confounders, including African genomic ancestry. Together, these findings add novel insights about the immunologic aspects of ageing supported by a large population-based cohort study that provides evidences that corroborate with the inflammaging proposal and subsidize the establishment of biomarkers for monitoring the health status of aged population.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Brazil
* Chemokine CXCL10
* Chemokine CXCL9
* Cohort Studies
* Female
* Humans
* Immunosenescence
* Interleukin-6
* Interleukin-8
* Logistic Models
* Male
* Middle Aged
* Sex Factors
|keywords=* Ageing
* Biomarkers
* CXCL8
* CXCL9
* Gender
* IL-6
* Population-based cohort
|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.12.006
}}
{{medline-entry
|title=Selected life-extending interventions reduce arterial [[CXCL10]] and macrophage colony-stimulating factor in aged mouse arteries.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28390264
|abstract=Cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Aging is the most predictive risk factor for CVD and is associated with arterial inflammation which contributes to increased CVD risk. Although age-related arterial inflammation has been described in both humans and animals, only a limited number of inflammatory mediators, cytokines and chemokines have been identified. In this investigation we sought to determine whether lifespan extending interventions, including crowded litter early life nutrient deprivation (CL), traditional lifelong caloric restriction (CR) and lifelong Rapamycin treatment (Rap) would attenuate age-related arterial inflammation using multi analyte profiling. Aortas from Young (4-6months), Old (22months), Old CL, Old CR and Old Rap mice were homogenized and cytokine concentrations were assessed using Luminex Multi Analyte Profiling. Chemokines involved in immune cell recruitment, such as [[CCL2]], [[CXCL9]], [[CXCL10]], GMCSF and MCSF, were increased in Old vs. Young (p<0.05). The age-related increase of [[CXCL10]] was prevented by CR (p<0.05 vs. Old). MSCF concentrations were lower in aortas of Rap treated mice (p<0.05 vs. Old). Interleukins (IL), IL-1α, IL-1β and IL-10, were also greater in Old vs. Young mice (p<0.05). These data demonstrate selected lifespan extending interventions can prevent or limit age-related increases in selected aortic chemokines.
|mesh-terms=* Aging
* Animals
* Arteries
* Caloric Restriction
* Cardiovascular Diseases
* Chemokine CCL2
* Chemokine CCL4
* Chemokine CXCL10
* Chemokines
* Cytokines
* Early Medical Intervention
* Interleukin-10
* Interleukin-1beta
* Interleukins
* Macrophage Colony-Stimulating Factor
* Male
* Mice
* Sirolimus
|keywords=* Aorta
* Caloric restriction
* Chemokine
* Cytokine
* Interleukin
* Rapamycin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544385
}}
{{medline-entry
|title=Strain specificities in cellular and molecular immunopathogenic mechanisms underlying development of experimental autoimmune encephalomyelitis in aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28284714
|abstract=To understand strain-specificities of immune system in aged rats and their immunopathological implications, CD4  T lymphocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis (EAE) was studied in two strains. Upon immunization for EAE, 22-24-month-old Albino Oxford (AO) rats developed milder neurological deficit of prolonged duration compared with their Dark Agouti (DA) counterparts. Consistently, they exhibited: (i) diminished neuroantigen-specific CD4  T lymphocyte generation in draining lymph nodes (reflecting lower density of high-affinity IL-2 receptor complex on their surface and higher CD4 FoxP3 CD25  regulatory cell frequency); (ii) less favorable spinal cord expression of [[CXCL12]] and [[CCL2]], and consequently diminished infiltration of neuroantigen-specific CD4  T lymphocytes, including highly pathogenic IL-17 IFN-γ  ones, and inflammatory monocytes into the spinal cord and (iii) subsequently impaired CD4  T lymphocyte reactivation/survival and differentiation into highly pathogenic IL-17  cells (reflecting downregulated expression of IL-1β, IL-6 and IL-23/p19). On the other hand, when the neurological deficit reached maximum/plateau, in AO rat spinal cord was found lower CD4 FoxP3 CD25  cell frequency followed by higher frequency of IL-10-producing CD8  T cells, which most likely also belong to regulatory T lymphocytes. Thus, the altered relation between regulatory T cell and effector CD4  T cell subsets was linked with persistence of mild neuroinflammation in AO rat EAE model.
|mesh-terms=* Aging
* Animals
* CD8-Positive T-Lymphocytes
* Cytokines
* Encephalomyelitis, Autoimmune, Experimental
* Female
* Rats
* Receptors, Interleukin-2
* Species Specificity
* Spinal Cord
* T-Lymphocytes, Regulatory
|keywords=* Aged rats
* EAE
* IL-10-producing T cells
* IL-17 IFN-γ  T lymphocytes
* Rat strain differences
|full-text-url=https://sci-hub.do/10.1016/j.mad.2017.03.001
}}
{{medline-entry
|title=Advanced atherosclerosis is associated with inflammation, vascular dysfunction and oxidative stress, but not hypertension.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28017665
|abstract=Although hypertension may involve underlying inflammation, it is unknown whether advanced atherosclerosis - a chronic inflammatory condition - can by itself promote hypertension. We thus tested if advanced atherosclerosis in chronically hypercholesterolemic mice is associated with systemic and end-organ inflammation, vascular dysfunction and oxidative stress, and whether blood pressure is higher than in control mice. Male ApoE  and wild-type (C57Bl6J) mice were placed on a high fat or chow diet, respectively, from 5 to 61 weeks of age. Expression of several cytokines (including IL-6, [[TNF]]-α, IFN-γ and/or IL-1β) was elevated in plasma, brain, and aorta of ApoE  mice. Aortic superoxide production was ∼3.5-fold greater, and endothelium-dependent relaxation was markedly reduced in aorta and mesenteric artery of ApoE  versus wild-type mice. There was no difference in blood pressure of aged ApoE  (104±3mmHg, n=13) and wild-type mice (113±1mmHg, n=18). To clarify any effects of aging alone, findings from 61 week-old wild-type mice were compared with those from young (8-12 weeks old) chow-fed wild-type mice. The data indicate that aging alone increased renal and aortic expression of numerous cytokines (including [[CCL2]], [[CCL7]] and IL-1β). Aging had no effect on blood pressure, systemic inflammation, oxidative stress or endothelial function. Despite systemic and end-organ inflammation, oxidative stress and endothelial dysfunction, advanced atherosclerosis does not necessarily result in elevated blood pressure.
|mesh-terms=* Animals
* Aorta
* Apolipoproteins E
* Atherosclerosis
* Blood Pressure
* Chemokine CCL2
* Chemokine CCL7
* Diet, High-Fat
* Disease Models, Animal
* Endothelium, Vascular
* Hypertension
* Inflammation
* Interferon-gamma
* Interleukin-1beta
* Interleukin-6
* Male
* Mesenteric Arteries
* Mice
* Mice, Inbred C57BL
* Oxidative Stress
* Superoxides
* Tumor Necrosis Factor-alpha
* Vascular Diseases
|keywords=* Aging
* Atherosclerosis
* Endothelial dysfunction
* Hypertension
* Inflammation
* Oxidative stress
|full-text-url=https://sci-hub.do/10.1016/j.phrs.2016.12.032
}}
{{medline-entry
|title=An attenuated immune response by Schwann cells and macrophages inhibits nerve regeneration in aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27459920
|abstract=Although peripheral nerves are capable of regeneration, advanced age decreases the potential for functional recovery after injury. The cellular mechanisms for this are not currently understood. Here, we performed sciatic nerve grafting with young (2 months old) and aged (18 months old) Brown-Norway male rats, in which 1 cm nerve grafts from young or aged rats were sutured into nerves of young or aged rats. Axons were allowed to regenerate until the nerve grafts and distal nerves were harvested at 1, 3, and 7 days and 2 and 6 weeks. At 6 weeks, our data suggested that young nerve grafts supported regeneration better than aged nerve grafts. In addition, myelin debris clearance was inhibited in young nerves when grafted into aged rats, but clearance was faster when aged nerves were grafted into young rats. Further analysis revealed that aged macrophages have delayed migration into injured nerve, and macrophages and Schwann cells from aged rats were less phagocytic for myelin debris in vitro. To understand these impairments, expression levels of pro- and anti-inflammatory cytokines were analyzed at 1 day after injury. Based on these levels, there was not a clear polarization to either an M1 or M2 phenotype; however, expression levels of IL-6, IL-10, [[CCL2]] (MCP1), and Arg-1 were decreased in aged nerves. Taken together, both macrophages and Schwann cells had attenuated responses to nerve injury in aged rats, leading to inefficient clearance of debris and impaired axonal regeneration.
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Chemokine CCL2
* Interleukin-10
* Interleukin-6
* Macrophages
* Male
* Nerve Regeneration
* Rats
* Schwann Cells
* Sciatic Nerve
|keywords=* Macrophages
* Nerve regeneration
* Schwann cells
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2016.05.004
}}
{{medline-entry
|title=Enhanced Ccl2-Ccr2 signaling drives more severe choroidal neovascularization with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26973110
|abstract=The impact of many inflammatory diseases is influenced by age-related changes in the activation of resident and circulating myeloid cells. In the eye, a major sight-threatening consequence of age-related macular degeneration is the development of severe choroidal neovascularization (CNV). To identify the molecular pathways and myeloid cell populations involved in this increased neovascular response, we characterized the immune status of murine choroid and retina during aging and in the context of experimental CNV. In the choroid, but not in the retina, advancing age is associated with proinflammatory upregulation of [[CCL2]]-[[CCR2]] signaling. Genetic excision of [[CCL2]] diminishes age-related inflammatory changes in the choroid, with reduced recruitment of proinflammatory myeloid cells and attenuation of CNV. These findings indicate that [[CCL2]]-driven recruitment of myeloid cells contributes to increased severity of CNV with age. Similar mechanisms may be involved in other age-related inflammatory diseases. 
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Chemokine CCL2
* Choroidal Neovascularization
* Mice, Inbred C57BL
* Mice, Knockout
* Receptors, CCR2
* Severity of Illness Index
* Signal Transduction
|keywords=* Aging
* CCL2
* Choroid
* Choroidal neovascularization
* Myeloid cells
* Retina
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2015.12.019
}}
{{medline-entry
|title=Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26924930
|abstract=Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, [[TNF]]-alpha and [[CCL2]] in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia. 

|keywords=* Agmatine
* Cell death
* High glucose
* Hyperglycemia
* Pro-inflammatory cytokines
* Senescence
* p21
* p53
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766111
}}
{{medline-entry
|title=Alterations in Monocyte Phenotypes and Functions after a Hip Fracture in Elderly Individuals: A 6-Month Longitudinal Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26812523
|abstract=Healthy elderly individuals are particularly prone to catastrophic events at any moment of their lives. One stressful event for individuals aged 65 and older is a fall that results in a fracture of the hip (HF). HF causes a state of inflammation that may affect immune responses. In this connection, we have reported that HF induced alterations in neutrophil functions. To assess the impact of HF on classical (cM), intermediate (iM) and non-classical (ncM) monocyte subsets. Distribution, functions (chemotaxis, phagocytosis, superoxide production and cytokine production), phenotype and activation (NF-x03BA;B and PI3K) were evaluated in monocyte subsets before surgery and 6 weeks and 6 months after the event. The distribution of cM and ncM was unchanged, but iM transiently increased before surgery. Sustained increases (iM response to [[CCL2]] and CX3CL1) and decreases (cM and ncM response to [[CCL2]]) in chemotaxis were observed. Phagocytosis and superoxide production were impaired in cM but not in iM or ncM. Sustained expression of HLA-DR occurred in cM but not in iM and ncM. Sustained decreased expression of CD11b occurred only in ncM. Sustained decreases (cM and ncM) and increases (iM) in [[CCR2]] expression were observed. An elevated expression of [[CX3CR1]] was found only in iM. cM produced elevated quantities of TNFα. There was a transient oxidative burst of production before surgery in iM and a sustained decrease in ncM. IL-10 production was severely impaired in cM and decreased in iM prior to surgery. Sustained activation (cM), inhibition (ncM) and transient activation (iM) of NF-x03BA;B were observed. Activation of PI3K was severely impaired in cM and ncM but was sustained in iM. HF had more impact on cM and ncM functions than on iM. HF triggered a switch in cM functions from phagocytic to inflammatory elevated TNFα-producing cells. These changes may impact clinical outcomes of HF with respect to inflammation, opportunistic infections and physical recovery.
|mesh-terms=* Aged
* Aging
* Chemotaxis
* Cytokines
* Female
* Hip Fractures
* Humans
* Longitudinal Studies
* Male
* Monocytes
* Perioperative Period
* Phagocytosis
* Phosphatidylinositol 3-Kinases
* Superoxides
* Tumor Necrosis Factor-alpha

|full-text-url=https://sci-hub.do/10.1159/000443142
}}
{{medline-entry
|title=Elevated Levels of Microbial Translocation Markers and [[CCL2]] Among Older HIV-1-Infected Men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26494772
|abstract=The aging of the human immunodeficiency virus type 1 (HIV-1)-infected population obligates a focus on the interaction between aging, comorbid conditions, and HIV-1. We recruited a cohort of HIV-1-infected men aged ≤ 35 years or ≥ 50 years who were receiving fully suppressive antiretroviral therapy (ART). We analyzed plasma markers of inflammation; T-cell activation, exhaustion, proliferation; and innate cellular subsets and functional capacity. Levels of lipopolysaccharide and the plasma marker of chemokine (C-C motif) ligand 2 were significantly elevated in older HIV-infected men despite comparable cellular phenotypes. Compared with similarly age-stratified uninfected subjects, older HIV-1-infected adults were also more frequently in the upper quartile of soluble [[CD14]] expression.
|mesh-terms=* Adult
* Aging
* Anti-HIV Agents
* Bacterial Translocation
* Biomarkers
* Chemokine CCL2
* Genotype
* HIV Infections
* HIV-1
* Humans
* Immunity, Innate
* Inflammation
* Lymphocyte Activation
* Male
* Middle Aged
* T-Lymphocytes
|keywords=* HIV-1
* chemokine
* inflammation
* monocytes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747622
}}
{{medline-entry
|title=[[APOE]] Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26446211
|abstract=Contrary to Alzheimer's disease (AD), the [[APOE]]2 allele increases and the [[APOE]]4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common [[APOE]]3 allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate in Cx3cr1-deficient mice due to the overexpression of [[APOE]], interleukin-6, and CC chemokine ligand 2 ([[CCL2]]). We here show using targeted replacement mice expressing the human [[APOE]] isoforms (TRE2, TRE3, and TRE4) that MPs of TRE2 mice express increased levels of [[APOE]], interleukin-6, and [[CCL2]] and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of [[APOE]]-dependent subretinal inflammation in Cx3cr1(GFP/GFP) mice, the [[APOE]]4 allele led to diminished [[APOE]] and [[CCL2]] levels and protected Cx3cr1(GFP/GFP) mice against harmful subretinal MP accumulation observed in Cx3cr1(GFP/GFP)TRE3 mice. Our study shows that pathogenic subretinal inflammation is [[APOE]] isoform-dependent and provides the rationale for the previously unexplained implication of the [[APOE]]2 isoform as a risk factor and the [[APOE]]4 isoform as a protective factor in AMD pathogenesis. The understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human [[APOE]] isoform-defining sequences at the mouse [[APOE]] chromosomal location and express the human [[APOE]] isoforms. Our study is the first to show how [[APOE]]2 provokes and [[APOE]]4 inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of [[APOE]] in inflammation and inflammation in AMD.
|mesh-terms=* Aging
* Animals
* Apolipoproteins E
* CX3C Chemokine Receptor 1
* Calcium-Binding Proteins
* Cells, Cultured
* Cytokines
* Disease Models, Animal
* Eye Proteins
* Female
* Gene Expression Regulation
* Humans
* Inflammation
* Lasers
* Macular Degeneration
* Male
* Membrane Proteins
* Mice
* Mice, Transgenic
* Microfilament Proteins
* Nerve Tissue Proteins
* Protein Isoforms
* Receptors, Chemokine
* Retina
|keywords=* apolipoprotein E
* mononuclear phagocyte
* neurodegeneration
* neuroinflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605380
}}
{{medline-entry
|title=Colorectal cancer-promoting activity of the senescent peritoneal mesothelium.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26284488
|abstract=Gastrointestinal cancers metastasize into the peritoneal cavity in a process controlled by peritoneal mesothelial cells (HPMCs). In this paper we examined if senescent HPMCs can intensify the progression of colorectal (SW480) and pancreatic (PSN-1) cancers in vitro and in vivo. Experiments showed that senescent HPMCs stimulate proliferation, migration and invasion of SW480 cells, and migration of PSN-1 cells. When SW480 cells were injected i.p. with senescent HPMCs, the dynamics of tumor formation and vascularization were increased. When xenografts were generated using PSN-1 cells, senescent HPMCs failed to favor their growth. SW480 cells subjected to senescent HPMCs displayed up-regulated expression of transcripts for various pro-cancerogenic agents as well as increased secretion of their products. Moreover, they underwent an epithelial-mesenchymal transition in the Smad 2/3-Snail1-related pathway. The search for mediators of senescent HPMC activity showed that increased SW480 cell proliferation was stimulated by IL-6, migration by [[CXCL8]] and [[CCL2]], invasion by IL-6, MMP-3 and uPA, and epithelial-mesenchymal transition by TGF-β1. Secretion of these agents by senescent HPMCs was increased in an NF-κB- and p38 MAPK-dependent mechanism. Collectively, our findings indicate that in the peritoneum senescent HPMCs may create a metastatic niche in which critical aspects of cancer progression become intensified. 
|mesh-terms=* Animals
* Cell Line, Tumor
* Cell Movement
* Cell Proliferation
* Cellular Senescence
* Colorectal Neoplasms
* Epithelial-Mesenchymal Transition
* Gene Expression Regulation, Neoplastic
* Humans
* Mice, SCID
* Neoplasm Invasiveness
* Pancreatic Neoplasms
* Paracrine Communication
* Peritoneal Neoplasms
* Peritoneum
* Signal Transduction
* Time Factors
* Tumor Microenvironment
|keywords=* cellular senescence
* gastrointestinal cancers
* mesothelial cells
* mice xenografts
* peritoneal cavity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745719
}}
{{medline-entry
|title=Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26235435
|abstract=Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish [[APP]] mutations (Tg[[APP]]) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aβ was detected at 4months in Tg[[APP]] and pre-plaque intracellular Aβ accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as [[CCL2]] and [[CCL5]] were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble [[CX3CL1]] decreased. A change in glial profile was only robustly detected at 6months in Tg-[[APP]] mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased [[CX3CL1]]. Bosutinib increased brain and blood IL-10 and [[CX3CL1]], suggesting a protective role for soluble [[CX3CL1]]. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation. 
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Aniline Compounds
* Animals
* Astrocytes
* Brain
* Cytokines
* Disease Models, Animal
* Enzyme Inhibitors
* Female
* Humans
* Intracellular Space
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Microglia
* Neuroimmunomodulation
* Nitriles
* Peptide Fragments
* Plaque, Amyloid
* Protein-Tyrosine Kinases
* Pyrimidines
* Quinolines
|keywords=* CX3CL1
* bosutinib
* inflammation
* nilotinib
* plaque
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2015.07.070
}}
{{medline-entry
|title=Neuroimmune and Neuropathic Responses of Spinal Cord and Dorsal Root Ganglia in Middle Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26241743
|abstract=Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that [[CD2]], CD3e, [[CD68]], CD45, [[TNF]]-α, [[IL6]], [[CCL2]], [[ATF3]] and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in [[CCL2]], and [[IL6]], and elevated [[ATF3]] mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased [[ATF3]]); whereas, levels of [[GFAP]] protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain. 
|mesh-terms=* Age Factors
* Aging
* Animals
* Antigens, CD
* Cytokines
* Ganglia, Spinal
* Male
* Microglia
* Neuralgia
* Nociception
* Rats
* Satellite Cells, Perineuronal
* Sciatic Neuropathy
* Spinal Cord

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524632
}}
{{medline-entry
|title=Microglial Kv1.3 Channels and P2Y12 Receptors Differentially Regulate Cytokine and Chemokine Release from Brain Slices of Young Adult and Aged Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26011191
|abstract=Brain tissue damage following stroke or traumatic brain injury is accompanied by neuroinflammatory processes, while microglia play a central role in causing and regulating neuroinflammation via production of proinflammatory substances, including cytokines and chemokines. Here, we used brain slices, an established in situ brain injury model, from young adult and aged mice to investigate cytokine and chemokine production with particular focus on the role of microglia. Twenty four hours after slice preparation, higher concentrations of proinflammatory cytokines, i.e. [[TNF]]-α and IL-6, and chemokines, i.e. [[CCL2]] and [[CXCL1]], were released from brain slices of aged mice than from slices of young adult mice. However, maximal microglial stimulation with LPS for 24 h did not reveal age-dependent differences in the amounts of released cytokines and chemokines. Mechanisms underlying microglial cytokine and chemokine production appear to be similar in young adult and aged mice. Inhibition of microglial Kv1.3 channels with margatoxin reduced release of IL-6, but not release of [[CCL2]] and [[CXCL1]]. In contrast, blockade of microglial P2Y12 receptors with PSB0739 inhibited release of [[CCL2]] and [[CXCL1]], whereas release of IL-6 remained unaffected. Cytokine and chemokine production was not reduced by inhibitors of Kir2.1 K  channels or adenosine receptors. In summary, our data suggest that brain tissue damage-induced production of cytokines and chemokines is age-dependent, and differentially regulated by microglial Kv1.3 channels and P2Y12 receptors. 
|mesh-terms=* Aging
* Animals
* Brain
* Chemokines
* Cytokines
* Gene Expression Regulation
* Kv1.3 Potassium Channel
* Lipopolysaccharides
* Mice
* Microglia
* Models, Biological
* Receptors, Purinergic P2Y12

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444306
}}
{{medline-entry
|title=[[CCL2]], [[CXCL8]], [[CXCL9]] and [[CXCL10]] serum levels increase with age but are not altered by treatment with hydroxychloroquine in patients with osteoarthritis of the knees.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25955863
|abstract=Osteoarthritis (OA) is a major cause of morbidity and incapacity in the elderly. This study evaluates serum levels of the chemokines [[CCL2]], [[CXCL8]], [[CXCL9]], and [[CXCL10]] in 16 patients with primary OA of the knees, and investigates how treatment with hydroxychloroquine (HCQ) for 4 months affects these chemokine levels. Thirteen elderly patients received a placebo. Healthy control groups consisted of 10 elderly individuals (age > 60 years) with no clinical or radiological evidence of OA (CT-O), and 10 young adult individuals, (CT-Y group, age < 40 years). The CT-Y group presented lower levels of all chemokines studied, in comparison to the other groups. HCQ treatment did not alter the serum levels of [[CCL2]] (P = 0.80), [[CXCL8]] (P = 0.76), [[CXCL9]] (P = 0.95) and [[CXCL10]] (P = 0.74) in OA patients. Hydroxychloroquine treatment did not alter the serum levels of [[CCL2]], [[CXCL8]], [[CXCL9]] or [[CXCL10]] in patients with OA of the knees, although increased serum levels correlated with aging for all subjects, including controls.
|mesh-terms=* Age Factors
* Aged
* Aging
* Antirheumatic Agents
* Biomarkers
* Case-Control Studies
* Chemokine CCL2
* Chemokine CXCL10
* Chemokine CXCL9
* Female
* Humans
* Hydroxychloroquine
* Interleukin-8
* Male
* Middle Aged
* Osteoarthritis, Knee
* Time Factors
* Treatment Outcome
* Up-Regulation
|keywords=* aging
* arthritis
* chemokines
* hydroxychloroquine
* pain
|full-text-url=https://sci-hub.do/10.1111/1756-185X.12589
}}
{{medline-entry
|title=Senescent dermal fibroblasts enhance stem cell migration through [[CCL2]]/[[CCR2]] axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25808810
|abstract=During aging, increases in the number of senescent cells are seen in various tissues. On the other hand, stem cells play crucial roles in tissue repair and homeostasis. Therefore, it is likely that stem cells give rise to new cells that replace senescent cells. However, how stem cells contribute to homeostasis in the dermis has not been elucidated. Here, we investigated the effects of factors secreted from senescent fibroblasts on stem cells. We found that senescent human dermal fibroblast (HDF) conditioned medium (CM) significantly enhanced stem cell migration compared with young HDF CM. The senescent HDF CM strongly secreted chemokine ligand 2 ([[CCL2]]). Furthermore, [[CCL2]] was found to enhance stem cell migration, and the inhibition of [[CCR2]], a receptor for [[CCL2]], reduced stem cell migration. These results suggest that senescent fibroblasts recruit stem cells by secreting various factors and that the [[CCL2]]/[[CCR2]] axis is one of the mechanisms underlying this phenomenon. 
|mesh-terms=* Cells, Cultured
* Cellular Senescence
* Chemokine CCL2
* Culture Media, Conditioned
* Dermis
* Fibroblasts
* Humans
* Mesenchymal Stem Cells
* Receptors, CCR2
* Up-Regulation
|keywords=* chemokine
* dermal fibroblasts
* mesenchymal stem cells
* senescence
* skin homeostasis
|full-text-url=https://sci-hub.do/10.1111/exd.12701
}}
{{medline-entry
|title=Age-associated changes in basal NF-κB function in human CD4  T lymphocytes via dysregulation of PI3 kinase.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25553802
|abstract=Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-κB is higher in purified and rested human CD4  T lymphocytes from older compared to younger individuals. This increase of NF-κB -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as [[CCL2]] and CXCL10. We demonstrate that NF-κB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-κB activity may contribute to the mild pro-inflammatory state of aging. 
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* CD4-Positive T-Lymphocytes
* Cells, Cultured
* Cytokines
* Female
* Humans
* Inflammation Mediators
* Male
* Middle Aged
* NF-kappa B
* Phosphatidylinositol 3-Kinase
* Phosphoinositide-3 Kinase Inhibitors
* Protein Kinase Inhibitors
* Signal Transduction
* Sirolimus
* Transcription, Genetic

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276789
}}
{{medline-entry
|title=IL-4 signaling drives a unique arginase /IL-1β  microglia phenotype and recruits macrophages to the inflammatory CNS: consequences of age-related deficits in IL-4Rα after traumatic spinal cord injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24966389
|abstract=Alternative activation of microglia/macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18-19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 ([[CCL2]]) expression, and diminished recruitment of IL-4Rα( ) macrophages to the injured spinal cord. Furthermore, the link between reduced IL-4Rα expression and reduced arginase, IL-1β, and [[CCL2]] expression was confirmed using adult IL-4Rα knock-out (IL-4Rα(KO)) mice. To better understand IL-4Rα-mediated regulation of active microglia, a series of studies was completed in mice that were peripherally injected with lipopolysaccharide and later provided IL-4 by intracerebroventricular infusion. These immune-based studies demonstrate that inflammatory-induced IL-4Rα upregulation on microglia was required for the induction of arginase by IL-4. In addition, IL-4-mediated reprogramming of active microglia enhanced neurite growth ex vivo and increased inflammatory gene expression (i.e., IL-1β and [[CCL2]]) and the corresponding recruitment of CCR2( )/IL-4Rα( )/arginase( ) myeloid cells in vivo. IL-4 reprogrammed active microglia to a unique and previously unreported phenotype (arginase( )/IL-1β( )) that augmented neurite growth and enhanced recruitment of peripheral IL-4Rα( ) myeloid cells to the CNS. Moreover, this key signaling cascade was impaired with age corresponding with reduced functional recovery after SCI. 
|mesh-terms=* Aging
* Animals
* Arginase
* Chemokine CCL2
* Disease Models, Animal
* Inflammation
* Interleukin-1beta
* Interleukin-4
* Macrophage Activation
* Macrophages
* Mice
* Microglia
* Neurites
* Receptors, Interleukin-4
* Signal Transduction
* Spinal Cord Injuries
|keywords=* IL-4
* M2a
* advanced age
* inflammation
* microglia
* spinal cord injury
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069360
}}
{{medline-entry
|title=Systemic inflammation impairs attention and cognitive flexibility but not associative learning in aged rats: possible implications for delirium.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24959140
|abstract=Delirium is a common and morbid condition in elderly hospitalized patients. Its pathophysiology is poorly understood but inflammation has been implicated based on a clinical association with systemic infection and surgery and preclinical data showing that systemic inflammation adversely affects hippocampus-dependent memory. However, clinical manifestations and imaging studies point to abnormalities not in the hippocampus but in cortical circuits. We therefore tested the hypothesis that systemic inflammation impairs prefrontal cortex function by assessing attention and executive function in aged animals. Aged (24-month-old) Fischer-344 rats received a single intraperitoneal injection of lipopolysaccharide (LPS; 50 μg/kg) or saline and were tested on the attentional set-shifting task (AST), an index of integrity of the prefrontal cortex, on days 1-3 post-injection. Plasma and frontal cortex concentrations of the cytokine TNFα and the chemokine [[CCL2]] were measured by ELISA in separate groups of identically treated, age-matched rats. LPS selectively impaired reversal learning and attentional shifts without affecting discrimination learning in the AST, indicating a deficit in attention and cognitive flexibility but not learning globally. LPS increased plasma TNFα and [[CCL2]] acutely but this resolved within 24-48 h. TNFα in the frontal cortex did not change whereas [[CCL2]] increased nearly threefold 2 h after LPS but normalized by the time behavioral testing started 24 h later. Together, our data indicate that systemic inflammation selectively impairs attention and executive function in aged rodents and that the cognitive deficit is independent of concurrent changes in frontal cortical TNFα and [[CCL2]]. Because inattention is a prominent feature of clinical delirium, our data support a role for inflammation in the pathogenesis of this clinical syndrome and suggest this animal model could be useful for studying that relationship further. 

|keywords=* CCL2
* aging neuroscience
* frontal cortex
* inflammation
* lipopolysaccharides
* rats
* set-shifting
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050637
}}
{{medline-entry
|title=Impaired innate mucosal immunity in aged mice permits prolonged Streptococcus pneumoniae colonization.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24082075
|abstract=Streptococcus pneumoniae is a frequent asymptomatic colonizer of the nasopharyngeal niche and only occasionally progresses toward infection. The burden of pneumococcal disease is particularly high in the elderly, and the mechanisms behind this increased susceptibility are poorly understood. Here we used a mouse model of pneumococcal carriage to study immunosenescence in the upper respiratory tract (URT). Nasal mucosa-associated lymphoid tissue (NALT) showed increased expression of Toll-like receptor 1, interleukin-1β, NLRp3 inflammasome, and [[CCL2]] in naive elderly compared to young animals. This suggests an increased proinflammatory expression profile in the NALT of aged mice at baseline. Simultaneously, we observed a more tolerogenic profile in respiratory epithelia of naive elderly compared to young adult mice with upregulation of the NF-κβ pathway inhibitor peroxisome proliferator-activated receptor gamma (PPARγ). After nasal instillation of pneumococci, pneumococcal colonization was prolonged in elderly mice compared to in young adults. The delay in clearance was associated with absent or delayed upregulation of a proinflammatory mediator(s) in the NALT, diminished influx of macrophages into the URT niche, and absent downregulation of PPARγ in respiratory epithelium, accompanied by diminished expression of cathelicidin (CRAMP) at the site of colonization. These findings suggest that unresponsiveness to pneumococcal challenge due to altered mucosal immune regulation is the key to increased susceptibility to disease in the elderly. 
|mesh-terms=* Age Factors
* Aging
* Animals
* Antimicrobial Cationic Peptides
* Bacterial Load
* Carrier Proteins
* Chemokine CCL2
* Disease Models, Animal
* Female
* Immunity, Innate
* Immunity, Mucosal
* Interleukin-1beta
* Macrophages
* Mice
* Mice, Inbred C57BL
* NF-kappa B
* NLR Family, Pyrin Domain-Containing 3 Protein
* Nasopharynx
* PPAR gamma
* Pneumococcal Infections
* Respiratory Mucosa
* Streptococcus pneumoniae
* Toll-Like Receptor 1

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837976
}}
{{medline-entry
|title=Effects of ethanol on immune response in the brain: region-specific changes in adolescent versus adult mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24033454
|abstract=Alcohol use occurs across the life span beginning in adolescence and continuing through adulthood. Ethanol (EtOH)-induced pathology varies with age and includes changes in neurogenesis, neurodegeneration, and glial cell activation. EtOH-induced changes in glial activation and immune activity are believed to contribute to EtOH-induced neuropathology. Recent studies indicate an emerging role of glial-derived neuroimmune molecules in alcohol abuse and addiction. Adolescent and adult C57BL/6 mice were treated via gavage with 6 g/kg EtOH for 10 days, and tissue was harvested 1 day post treatment. We compared the effects of EtOH on chemokine and cytokine expression and astrocyte glial fibrillary acidic protein ([[GFAP]]) immunostaining and morphology in the hippocampus, cerebellum, and cerebral cortex. EtOH increased mRNA levels of the chemokine [[CCL2]]/MCP-1 in all 3 regions of adult mice relative to controls. The cytokine interleukin-6 (IL-6) was selectively increased only in the adult cerebellum. EtOH did not affect mRNA levels of the cytokine tumor necrosis factor-alpha ([[TNF]]-α) in any of these brain regions in adult animals. Interestingly, [[CCL2]], IL-6, and [[TNF]]-α mRNA levels were not increased in the hippocampus, cerebellum, or cortex of adolescent mice. EtOH treatment of adult and adolescent mice resulted in increased [[GFAP]] immunostaining. Collectively, these data indicate an age- and region-specific susceptibility to EtOH regulation of neuroinflammatory and addiction-related molecules as well as astrocyte phenotype. These studies may have important implications concerning differential alcohol-induced neuropathology and alcohol addiction across the life span.
|mesh-terms=* Aging
* Animals
* Astrocytes
* Brain
* Central Nervous System Depressants
* Cerebellum
* Cerebral Cortex
* Chemokine CCL2
* DNA, Complementary
* Ethanol
* Glial Fibrillary Acidic Protein
* Hippocampus
* Immunity
* Immunity, Cellular
* Immunohistochemistry
* Interleukin-6
* Mice, Inbred C57BL
* RNA
* Real-Time Polymerase Chain Reaction
* Tumor Necrosis Factor-alpha
|keywords=* Adolescent
* Adult
* Astrocyte
* CCL2
* Neuroinflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872252
}}
{{medline-entry
|title=Aging enhances the basal production of IL-6 and [[CCL2]] in vascular smooth muscle cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22034510
|abstract=Increased circulating cytokine levels are a prominent feature of aging that may contribute to atherosclerosis. However, the role vascular cells play in chronic inflammation induced by aging is not clear. Here, we examined the role of aging on inflammatory responses of vascular cells. In an ex vivo culture system, we examined the inflammatory response of aortas from young (2-4 months) and aged (16-18 months) mice under nonstimulatory conditions. We found that basal levels of interleukin-6 were increased in aged aortas. Aged aortic vascular smooth muscle cells (VSMC) exhibited a higher basal secretion of interleukin-6 than young VSMC. Gene and protein expression analysis revealed that aged VSMC exhibited upregulation of chemokines (eg, [[CCL2]]), adhesion molecules (eg, intracellular adhesion molecule 1), and innate immune receptors (eg, Toll-like receptor [TLR] 4), which all contribute to atherosclerosis. Using VSMC from aged TL4(-/-) and Myd88(-/-) mice, we demonstrate that signaling via [[TLR4]] and its signal adaptor, MyD88, are in part responsible for the age-elevated basal interleukin-6 response. Aging induces a proinflammatory phenotype in VSMC due in part to increased signaling of [[TLR4]] and MyD88. Our results provide a potential explanation as to why aging leads to chronic inflammation and enhanced atherosclerosis.
|mesh-terms=* Aging
* Animals
* Aorta, Thoracic
* Atherosclerosis
* Cells, Cultured
* Chemokine CCL2
* Female
* Interleukin-6
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Myeloid Differentiation Factor 88
* Myocytes, Smooth Muscle
* Signal Transduction
* Toll-Like Receptor 4
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241880
}}
{{medline-entry
|title=Systemic DNA damage related to cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21558390
|abstract=The importance of bystander effects is becoming more appreciated, as studies show they may affect the course of cancer and other chronic diseases. The term "bystander effects" refers to changes in naïve cells sharing the same milieu with cells that have been damaged. Bystander cells may be in contact with, or distant from, damaged cells. In addition, it has been shown in culture that not only physically damaged cells, but also cells that have become abnormal (i.e., cancerous or senescent) may induce bystander effects. Recently, we have shown a similar effect in animals. Mice harboring subcutaneous tumors exhibited elevated levels of DNA damage in distant organs. In contrast to cell culture, immune cells seemed to be involved in tumor-induced bystander effects in animals because [[CCL2]]-null tumor-bearing mice did not exhibit increased distant DNA damage. Here, we discuss some of the implications of these observations.
|mesh-terms=* Aging
* Animals
* Bystander Effect
* Chemokine CCL2
* Clinical Trials as Topic
* DNA Damage
* Epigenesis, Genetic
* Gene Expression Regulation, Neoplastic
* Humans
* Inflammation
* Mice
* Mice, Transgenic
* Models, Biological
* Neoplasm Metastasis
* Neoplasms

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096754
}}
{{medline-entry
|title=Age-dependent regenerative responses in the striatum and cortex after hypoxia-ischemia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18985054
|abstract=Regenerative responses after hypoxia-ischemia (HI) were investigated in the immature (P9) and juvenile (P21) mouse striatum and cortex by postischemic 5-bromo-2-deoxyuridine labeling and phenotyping of labeled cells 4 weeks later. HI stimulated the formation of new cells in striatum and cortex in immature, growing brains (P9), but when brain growth was finished (P21) proliferation could be stimulated only in striatum, not in cortex. However, the relative increase was higher in P21 (460%) than P9 striatum (50%), though starting from a lower level at P21. Starting from this lower level, HI-induced proliferation in P21 striatum reached the same level as in P9 striatum, but not higher. Phenotyping revealed that low levels of neurogenesis were still present in nonischemic P9 cortex and striatum, but only in striatum at P21. Ischemia-induced neurogenesis was found only in P9 striatum. Ischemia-induced gliogenesis occurred in P9 and P21 striatum as well as P9 cortex, but not in P21 cortex. Hence, the regenerative response was stronger in striatum than cortex, and stronger in P9 than P21 cortex. The biggest ischemia-induced change was the 49-fold increase in P21 striatal microglia, and this was accompanied by increased inflammation, as judged by the size and numbers of [[CCL2]]- and interleukin-18-positive cells.
|mesh-terms=* Aging
* Animals
* Biomarkers
* Bromodeoxyuridine
* Cell Differentiation
* Cerebrum
* Chemokine CCL2
* Hypoxia-Ischemia, Brain
* Interleukin-18
* Male
* Mice
* Mice, Inbred C57BL
* Neurogenesis
* Phenotype

|full-text-url=https://sci-hub.do/10.1038/jcbfm.2008.124
}}
{{medline-entry
|title=Increase of CXC chemokine [[CXCL10]] and CC chemokine [[CCL2]] serum levels in normal ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/16697212
|abstract=No study has evaluated contemporaneously serum CXC and CC chemokines changes in normal ageing. Serum levels of [[CXCL10]] (s[[CXCL10]]) (CXC) and [[CCL2]] (s[[CCL2]]) (CC) prototype chemokines have been measured in 164 healthy subjects, from 10 to 79 years of age (82 males/82 females). By simple regression analysis, s[[CXCL10]] and s[[CCL2]] were significantly related with increasing age (r=0.32, p<0.001; r=0.31, p<0.0001, respectively), and with each other (r=0.30, p=0.0004). In a multiple linear regression model, only age and s[[CCL2]] were significantly related to s[[CXCL10]] levels (p<0.001); age and s[[CXCL10]] were significantly related to s[[CCL2]] levels (p<0.001). Subjects with high s[[CXCL10]] levels (>150 pg/ml) were not significantly associated with those with high s[[CCL2]] levels (>559 pg/ml). This study, performed in healthy subjects on an age gradient, demonstrates an increase of s[[CXCL10]] and s[[CCL2]] with advancing age; the differential increase of s[[CXCL10]] or s[[CCL2]] may reflect a general shift towards Th1 or Th2 cytokines pattern, respectively.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aging
* Chemokine CCL2
* Chemokine CXCL10
* Chemokines, CXC
* Child
* Cytokines
* Female
* Humans
* Male
* Middle Aged
* Regression Analysis
* Thyroid Gland
* Ultrasonography

|full-text-url=https://sci-hub.do/10.1016/j.cyto.2006.03.012
}}