Редактирование: CXCL1 (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=Cerebrovascular Senescence Is Associated With Tau Pathology in Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33041998
|abstract=Alzheimer's Disease (AD) is associated with neuropathological changes, including aggregation of tau neurofibrillary tangles (NFTs) and amyloid-beta plaques. Mounting evidence indicates that vascular dysfunction also plays a key role in the pathogenesis and progression of AD, in part through endothelial dysfunction. Based on findings in animal models that tau pathology induces vascular abnormalities and cellular senescence, we hypothesized that tau pathology in the human AD brain leads to vascular senescence. To explore this hypothesis, we isolated intact microvessels from the dorsolateral prefrontal cortex (PFC, BA9) from 16 subjects with advanced Braak stages (Braak V/VI, B3) and 12 control subjects (Braak 0/I/II, B1), and quantified expression of 42 genes associated with senescence, cell adhesion, and various endothelial cell functions. Genes associated with endothelial senescence and leukocyte adhesion, including [[SERPINE1]] (PAI-1), [[CXCL8]] (IL8), [[CXCL1]], [[CXCL2]], ICAM-2, and [[TIE1]], were significantly upregulated in B3 microvessels after adjusting for sex and cerebrovascular pathology. In particular, the senescence-associated secretory phenotype genes [[SERPINE1]] and [[CXCL8]] were upregulated by more than 2-fold in B3 microvessels after adjusting for sex, cerebrovascular pathology, and age at death. Protein quantification data from longitudinal plasma samples for a subset of 13 ([i]n[/i] = 9 B3, [i]n[/i] = 4 B1) subjects showed no significant differences in plasma senescence or adhesion-associated protein levels, suggesting that these changes were not associated with systemic vascular alterations. Future investigations of senescence biomarkers in both the peripheral and cortical vasculature could further elucidate links between tau pathology and vascular changes in human AD.

|keywords=* Alzheimer's disease
* endothelial senescence
* gene expression
* neurofibrillary tangles
* plasma biomarkers
* tau pathology
* vascular dysfunction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525127
}}
{{medline-entry
|title=Flavonoids from Scutellaria baicalensis inhibit senescence-associated secretory phenotype production by interrupting IκBζ/C/EBPβ pathway: Inhibition of age-related inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32554301
|abstract=Prolonged exposure to the senescence-associated secretory phenotype (SASP) with age leads to chronic low-grade inflammation in neighboring cells and tissues, causing many chronic degenerative diseases. The effects on SASP production of the ethanol extract from Scutellaria radix and 17 isolated flavonoid constituents were examined in vitro and in vivo. Cellular senescence was induced by bleomycin. Expression of the SASP and cell signaling molecules was detected using ELISA, RT-qPCR, Western blotting, and immunofluorescence staining. To investigate the in vivo effects, 21-month-old aged rats were used. The ethanol extract and 5 compounds including 1 (Oroxylin A; 5,7-dihydroxy-6-methoxyflavone), 5 (2',6',5,7-tetrahydroxy-8-methoxyflavone), 8 (2',5,7-trihydroxyflavone), 10 (2',5,7-trihydroxy-8-methoxyflavone) and 11 (2',5,7-trihydroxy-6-methoxyflavone) potently reduced IL-6 and IL-8 production and gene expression of the SASP, including IL-1α, IL-1β, IL-6, IL-8, GM-CSF, [[CXCL1]], MCP-2, and MMP-3. This finding indicates the important role of the B-ring 2'‑hydroxyl group in flavonoid molecules. Furthermore, compounds 8 and 11, the strongest SASP inhibitors, decreased the expression of IκBζ and C/EBPβ protein without affecting either BrdU uptake or the expression of senescence markers, such as pRb and p21. Finally, the oral administration of compound 8 to aged rats at 2 and 4 mg/kg/day for 10 days significantly inhibited the gene expression of SASP and IκBζ in kidneys. This is the first report of the strong SASP inhibitory action of flavonoids from Scutellaria radix on in vitro and in vivo senescence models. The inhibitory action was shown to be mediated mainly by interfering with the IκBζ/C/EBPβ signaling pathway. Targeting production of the SASP using flavonoids from Scutellaria radix or its extract might help reduce low-grade sterile inflammation and control age-related diseases.

|keywords=* C/EBPβ
* Chronic low-grade inflammation
* IκBζ
* SASP
* Scutellaria baicalensis
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.phymed.2020.153255
}}
{{medline-entry
|title=Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32284366
|abstract=[i]Clostridioides[/i] (formerly [i]Clostridium[/i]) [i]difficile[/i] is the most common cause of hospital-acquired infection, and advanced age is a risk factor for [i]C. difficile[/i] infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of [i]C. difficile[/i] infection. However, the specific impact of aging on immune responses during [i]C. difficile[/i] infection remains to be well described. This study explores the effect of age on cellular and cytokine immune responses during [i]C. difficile[/i] infection. Young mice (2 to 3 months old) and aged mice (22 to 28 months old) were rendered susceptible to [i]C. difficile[/i] infection with the antibiotic cefoperazone and then infected with [i]C. difficile[/i] strains with varied disease-causing potentials. We observe that the host age and the infecting [i]C. difficile[/i] strain influenced the severity of disease associated with infection. Tissue-specific CD45  immune cell responses occurred at the time of peak disease severity in the ceca and colons of all mice infected with a high-virulence strain of [i]C. difficile[/i]; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice, with a corresponding decrease in circulating [[CXCL1]], an important neutrophil recruiter and activator. Interestingly, this lack of intestinal granulocyte response in aged mice during severe [i]C. difficile[/i] infection was accompanied by a simultaneous increase in circulating white blood cells, granulocytes, and interleukin 17A (IL-17A). These findings demonstrate that age-related alterations in neutrophils and eosinophils and systemic cytokine and chemokine responses are associated with severe [i]C. difficile[/i] infection and support a key role for intestinal eosinophils in mitigating [i]C. difficile[/i]-mediated disease severity.

|keywords=* Clostridioides difficile

* aging
* eosinophils
* gastrointestinal infection
* innate immunity
* intestinal colonization
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240091
}}
{{medline-entry
|title=A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32184029
|abstract=A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72  (C9 ) ALS patients to derive neuronal progenitor cells. We demonstrated that C9  and neurotypic neuronal progenitor cells differentiate into neurons. The C9  neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9  neurons. Moreover, C9  neurons expressed high levels of mRNA for [[CXCL8]], a chemokine overexpressed by senescent cells, while media from C9  neurons contained significant levels of [[CXCL8]], [[CXCL1]], [[IL13]], IP10, [[CX3CL1]], and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.
|mesh-terms=* Amyotrophic Lateral Sclerosis
* C9orf72 Protein
* Cell Cycle
* Cells, Cultured
* Cellular Senescence
* DNA Repeat Expansion
* Frontotemporal Dementia
* Gene Expression
* Gene Expression Regulation, Developmental
* Humans
* Induced Pluripotent Stem Cells
* Interleukin-8
* RNA, Messenger
* Stem Cells
|keywords=* Amyotrophic lateral sclerosis
* Cell cycle re-entry
* Frontotemporal dementia
* Senescence
* Senescence-associated secretory phenotype
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166179
}}
{{medline-entry
|title=Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32026570
|abstract=To determine whether muscle disuse after a spinal cord injury (SCI) produces elevated markers of cellular senescence and induces markers of the senescence-associated secretory phenotypes (SASPs) in paralyzed skeletal muscle. Four-month-old male Sprague-Dawley rats received a moderate-severe (250 kiloDyne) T-9 contusion SCI or Sham surgery and were monitored over 2 weeks, and 1-, 2-, or 3 months. Animals were sacrificed via isoflurane overdose and terminal exsanguination and the soleus was carefully excised and snap frozen. Protein expression of senescence markers p53, p27, and p16 was determined from whole soleus lysates using Western immunoblotting and RT-qPCR was used to determine the soleus gene expression of IL-1α, IL-1β, IL-6, [[CXCL1]], and TNFα. SCI soleus muscle displayed 2- to 3-fold higher total p53 protein expression at 2 weeks, and at 1 and 2 months when compared with Sham. p27 expression was stable across all groups and timepoints. p16 protein expression was lower at 3 months in SCI versus Sham, but not earlier timepoints. Gene expression was relatively stable between groups at 2 weeks. There were Surgery x Time interaction effects for IL-6 and TNFα mRNA expression but not for IL-1α, IL-1β, or [[CXCL1]]. There were no main effects for time or surgery for IL-1α, IL-1β, or [[CXCL1]], but targeted t tests showed reductions in IL-1α and [[CXCL1]] in SCI animals compared to Sham at 3 months and IL-1β was reduced in SCI animals compared to Sham animals at the 2-month timepoint. The elevation in p53 does not appear consistent with the induction of SASP because mRNA expression of cytokines associated with senescence was not uniformly upregulated and, in some instances, was downregulated in the early chronic phase of SCI.

|keywords=* SASP
* cytokines
* inflammation
* paralysis
* senescence
* spinal cord injury
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002538
}}
{{medline-entry
|title=Crucial role of the terminal complement complex in chondrocyte death and hypertrophy after cartilage trauma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31981738
|abstract=Innate immune response and particularly terminal complement complex (TCC) deposition are thought to be involved in the pathogenesis of posttraumatic osteoarthritis. However, the possible role of TCC in regulated cell death as well as chondrocyte hypertrophy and senescence has not been unraveled so far and was first addressed using an ex vivo human cartilage trauma-model. Cartilage explants were subjected to blunt impact (0.59 J) and exposed to human serum (HS) and cartilage homogenate (HG) with or without different potential therapeutics: [[RIPK1]]-inhibitor Necrostatin-1 (Nec), caspase-inhibitor zVAD, antioxidant N-acetyl cysteine (NAC) and TCC-inhibitors aurintricarboxylic acid (ATA) and clusterin (CLU). Cell death and hypertrophy/senescence-associated markers were evaluated on mRNA and protein level. Addition of HS resulted in significantly enhanced TCC deposition on chondrocytes and decrease of cell viability after trauma. This effect was potentiated by HG and was associated with expression of [[RIPK3]], [[MLKL]] and [[CASP8]]. Cytotoxicity of HS could be prevented by heat-inactivation or specific inhibitors, whereby combination of Nec and zVAD as well as ATA exhibited highest cell protection. Moreover, HS HG exposition enhanced the gene expression of [[CXCL1]], IL-8, [[RUNX2]] and [[VEGFA]] as well as secretion of IL-6 after cartilage trauma. Our findings imply crucial involvement of the complement system and primarily TCC in regulated cell death and phenotypic changes of chondrocytes after cartilage trauma. Inhibition of TCC formation or downstream signaling largely modified serum-induced pathophysiologic effects and might therefore represent a therapeutic target to maintain the survival and chondrogenic character of cartilage cells.

|keywords=* Aurintricarboxylic acid
* Cartilage trauma
* Hypertrophy
* Regulated cell death
* Senescence
* Terminal complement complex
|full-text-url=https://sci-hub.do/10.1016/j.joca.2020.01.004
}}
{{medline-entry
|title=Systemic Inflammation and the Increased Risk of Inflamm-Aging and Age-Associated Diseases in People Living With HIV on Long Term Suppressive Antiretroviral Therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31507593
|abstract=The ART program in low- and middle-income countries (LMIC) like India, follows a public health approach with a standardized regimen for all people living with HIV (PLHIV). Based on the evidence from high-income countries (HIC), the risk of an enhanced, and accentuated onset of premature-aging or age-related diseases has been observed in PLHIV. However, very limited data is available on residual inflammation and immune activation in the populations who are on first-generation anti-HIV drugs like zidovudine and lamivudine that have more toxic side effects. Therefore, the aim of the present study was to evaluate the levels of systemic inflammation and understand the risk of age-associated diseases in PLHIV on long-term suppressive ART using a large number of biomarkers of inflammation and immune activation. Blood samples were obtained from therapy naïve PLHIV (Pre-ART, [i]n[/i] = 43), PLHIV on ART for >5 years (ART, [i]n[/i] = 53), and HIV-negative healthy controls (HIVNC, [i]n[/i] = 41). Samples were analyzed for 92 markers of inflammation, sCD14, sCD163, and telomere length. Several statistical tests were performed to compare the groups under study. Multivariate linear regression was used to investigate the associations. Despite a median duration of 8 years of successful ART, sCD14 ([i]p[/i] < 0.001) and sCD163 ([i]p[/i] = 0.04) levels continued to be significantly elevated in ART group as compared to HIVNC. Eleven inflammatory markers, including 4E-BP1, [[ADA]], [[CCL23]], [[CD5]], [[CD8A]], [[CST5]], [[MMP1]], NT3, [[SLAMF1]], TRAIL, and TRANCE, were found to be significantly different ([i]p[/i] < 0.05) between the groups. Many of these markers are associated with age-related co-morbidities including cardiovascular disease, neurocognitive decline and some of these markers are being reported for the first time in the context of HIV-induced inflammation. Linear regression analysis showed a significant negative association between HIV-1-positivity and telomere length ([i]p[/i] < 0.0001). In ART-group [[CXCL1]] ([i]p[/i] = 0.048) and TGF-α ([i]p[/i] = 0.026) showed a significant association with the increased telomere length and IL-10RA was significantly associated with decreased telomere length ([i]p[/i] = 0.042). This observation warrants further mechanistic studies to generate evidence to highlight the need for enhanced treatment monitoring and special interventions in HIV-infected individuals.
|mesh-terms=* Adult
* Aging
* Anti-HIV Agents
* Antiretroviral Therapy, Highly Active
* Biomarkers
* CD4 Lymphocyte Count
* Computational Biology
* Cross-Sectional Studies
* Disease Susceptibility
* Duration of Therapy
* Female
* HIV Infections
* Humans
* Inflammation
* Male
* Metabolome
* Metabolomics
* Middle Aged
* Proteomics
* Telomere Homeostasis
* Viral Load
|keywords=* HIV
* India
* LMIC (lower middle income country)
* inflammation markers
* long term antiretroviral therapy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718454
}}
{{medline-entry
|title=Inflammatory and Senescent Phenotype of Pancreatic Stellate Cells Induced by Sqstm1 Downregulation Facilitates Pancreatic Cancer Progression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31182922
|abstract=Pancreatic ductal adenocarcinoma (PDAC) has unique microenvironment with extensive infiltration of fibroblasts, which are mainly derived from the resident pancreatic stellate cells (PaSCs). As activated PaSCs constitute a major contributor to pancreatic cancer progression, the mechanisms underlying their activation have been being intensively studied. Previous studies showed that Sequestosome-1 (sqstm1) can modulate the functional status of fibroblasts in cancer. Here, we further delineated the role of sqstm1 in PaSCs. The analysis of PDAC patient samples revealed reduction of sqstm1 expression in activated PaSCs in both mRNA and protein level. Downregulated sqstm1 via shRNA in PaSCs led to an inflammatory and senescent phenotype with increased IL8, [[CXCL1]], and [[CXCL2]] expression. Further analysis demonstrated that increased intracellular reactive oxygen species level contributed to the senescence in sqstm1-downregulated PaSCs. This was mediated via impaired NRF2 activity since reduced sqstm1 resulted in accumulation of [[KEAP1]]. Meanwhile, we found that sqstm1 degradation caused by enhanced autophagy was not associated with transformation of senescent phenotype. At last, the data revealed that sqstm1-downregulated PaSCs promoted pancreatic tumor cell growth, invasion, and macrophage phenotype transformation. Collectively, the current study indicated that sqstm1 controlled transformation of senescent phenotype of PaSCs, which in turn is pro-tumorigenic.
|mesh-terms=* Animals
* Carcinoma, Pancreatic Ductal
* Cell Line, Tumor
* Chemokine CXCL1
* Chemokine CXCL2
* Female
* Fluorescent Antibody Technique
* Humans
* Immunoblotting
* Immunohistochemistry
* Interleukin-8
* Mice
* Mice, Inbred BALB C
* Mice, Nude
* Pancreatic Neoplasms
* Pancreatic Stellate Cells
* RNA, Small Interfering
* Reactive Oxygen Species
* Real-Time Polymerase Chain Reaction
* Sequestosome-1 Protein
|keywords=* pancreatic adenocarcinoma
* pancreatic stellate cells
* reactive oxygen species
* senescence
* sqstm1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535784
}}
{{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=Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30617300
|abstract=Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral clearance or a pathological host immune response is unknown. Here we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines [[CXCL1]] and [[CXCL2]] during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro. Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.
|mesh-terms=* Aging
* Animals
* Cell Count
* Cellular Senescence
* Chemokine CXCL1
* Chemokine CXCL2
* Chemotaxis
* Epithelial Cells
* Humans
* Influenza, Human
* Lung
* Mice
* Mice, Inbred C57BL
* Mortality
* Neutrophils
* Survival Analysis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375784
}}
{{medline-entry
|title=Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30505308
|abstract=Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral [i]E. coli[/i] K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 μl vehicle solution ([i]n[/i] = 19) or with 250 μl vehicle solution only as controls ([i]n[/i] = 19), 12 h and 30 min prior to intracerebral [i]E. coli[/i] K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1β, IL-6, [[MIP]]-1α, and [[CXCL1]] in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group ([i]P[/i] = 0.031). PEA prophylaxis delayed the onset of clinical symptoms ([i]P[/i] = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals ([i]P[/i] ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals ([i]P[/i] = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.
|mesh-terms=* Aging
* Amides
* Animals
* Anti-Inflammatory Agents, Non-Steroidal
* Cerebellum
* Cytokines
* Dietary Supplements
* Disease Models, Animal
* Escherichia coli
* Ethanolamines
* Inflammation
* Kaplan-Meier Estimate
* Meningitis, Escherichia coli
* Mice
* Mice, Inbred C57BL
* Microglia
* Palmitic Acids
* Spleen
* Statistics, Nonparametric
* Survival Rate
|keywords=* Escherichia coli
* aging
* antimicrobial stewardship
* endocannabinoid
* immunomodulation
* lipidomics
* microglia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250830
}}
{{medline-entry
|title=The Role of Pulmonary and Systemic Immunosenescence in Acute Lung Injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30090646
|abstract=Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited. Here, we investigated the immune response at pulmonary, systemic and cellular level in young (2-3 months) and old (18-19 months) C57BL/6J mice to localize and characterize effects of immunosenescence in ALI. ALI was induced by intranasal lipopolysaccharide (LPS) application and the animals were sacrificed 24 or 72 h later. Pulmonary inflammation was investigated by analyzing histopathology, bronchoalveolar lavage fluid (BALF) cytometry and cytokine expression. Systemic serum cytokine expression, spleen lymphocyte populations and the gut microbiome were analyzed, as well as activation of alveolar and bone marrow derived macrophages (BMDM) [i]in vitro[/i]. Pulmonary pathology of ALI was more severe in old compared with young mice. Old mice showed significantly more inflammatory cells and pro-inflammatory cyto- or chemokines (TNFα, IL-6, MCP-1, [[CXCL1]], [[MIP]]-1α) in the BALF, but a delayed expression of cytokines associated with activation of adaptive immunity and microbial elimination (IL-12 and IFNγ). Alveolar macrophages, but not BMDM, of old mice showed greater activation after [i]in vivo[/i] and [i]in vitro[/i] stimulation with LPS. No systemic enhanced pro-inflammatory cytokine response was detected in old animals after LPS exposure, but a delayed expression of IL-12 and IFNγ. Furthermore, old mice had less CD8  T-cells and NK cells and more regulatory T-cells in the spleen compared with young mice and a distinct gut microbiome structure. The results of our study show an increased alveolar macrophage activation and pro-inflammatory signaling in the lungs, but not systemically, suggesting a key role of senescent alveolar macrophages in ALI. A decrease in stimulators of adaptive immunity with advancing age might further promote the susceptibility to a worse prognosis in ALI in elderly.

|keywords=* acute lung injury
* alveolar macrophages
* immunosenescence
* lipopolysaccharide
* pulmonary inflammation
* systemic inflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065297
}}
{{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=Aerobic Exercise Protects from Pseudomonas aeruginosa-Induced Pneumonia in Elderly Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29843140
|abstract=Pseudomonas aeruginosa (PS) infection results in severe morbidity and mortality, especially in immune-deficient populations. Aerobic exercise (AE) modulates the immune system, but its effects on the outcomes of pulmonary PS infection in elderly mice are unknown. BALB/c mice (24 weeks old) were randomized to sedentary, exercise (EX), PS, and PS   EX groups for the acute experimental setting, and PS and PS   EX groups for the chronic setting. Low-intensity AE was performed for 5 weeks, 60 min/day; 24 h after the final AE session, mice were inoculated with 5 × 104 colony-forming units (CFU) of PS, and 24 h and 14 days after PS inoculation, mice were studied. AE inhibited PS colonization (p < 0.001) and lung inflammation (total cells, neutrophils, lymphocytes [p < 0.01] in bronchoalveolar lavage [BAL]), with significant differences in BAL levels of IL-1β (p < 0.001), IL-6 (p < 0.01), [[CXCL1]] (p < 0.001), and [[TNF]]-α (p < 0.001), as well as parenchymal neutrophils (p < 0.001). AE increased BAL levels of IL-10 and parenchymal (p < 0.001) and epithelial (p < 0.001) IL-10 expression, while epithelial (p < 0.001) and parenchymal (p < 0.001) NF-κB expression was decreased. AE diminished pulmonary lipid peroxidation (p < 0.001) and increased glutathione peroxidase (p < 0.01). Pre-incubation of BEAS-2B with IL-10 inhibited PS-induced epithelial cell expression of [[TNF]]-α (p < 0.05), [[CD40]] (p < 0.01), and dichlorodihydrofluorescein diacetate (p < 0.05). AE inhibits PS-induced lung inflammation and bacterial colonization in elderly mice, involving IL-10/NF-κB, and redox signaling.
|mesh-terms=* Aging
* Animals
* Disease Models, Animal
* Exercise
* Glutathione Peroxidase
* Humans
* Interleukin-10
* Lipid Peroxidation
* Lung
* Mice
* Mice, Inbred BALB C
* NF-kappa B
* Neutrophils
* Physical Conditioning, Animal
* Pneumonia
* Pseudomonas Infections
* Pseudomonas aeruginosa
* Signal Transduction
|keywords=* Cytokines
* Elderly
* Exercise immunology
* Physical training
* Pseudomonas
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757150
}}
{{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 decline of the acute local inflammation response: a mitigating role for the adenosine A  receptor.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29064819
|abstract=Aging is accompanied by an increase in markers of innate immunity. How aging affects neutrophil functions remains of debate.The adenosine A  receptor (A R), essential to the resolution of inflammation, modulates neutrophil functions. We sought to determine whether or not A R protects against the effects of aging. We monitored neutrophil influx, viability, and activation as well as cytokine accumulation in wild-type (WT) and A R-knockout mice (KO) at three different ages.Several readouts decreased with aging: neutrophil counts in dorsal air pouches (by up to 55%), neutrophil viability (by up to 56%), elastase and total protein in exudates (by up to 80%), and local levels of cytokines (by up to 90%). Each of these parameters was significantly more affected in A R-KO mice. [[CXCL1]]-3 levels were largely unaffected. The effects of aging were not observed systemically. Preventing neutrophil influx into the air pouch caused a comparable cytokine pattern in young WT mice. Gene expression (mRNA) in leukocytes was affected, with [[CXCL1]] and [[CCL4]] increasing and with [[TNF]] and IL-1α decreasing. Aging has deleterious effects on the acute inflammatory response and neutrophil-related activities, and defective migration appears as an important factor. A functional A R signaling pathway delays some of these.
|mesh-terms=* Aging
* Animals
* Chemotaxis, Leukocyte
* Inflammation
* Mice
* Mice, Knockout
* Neutrophils
* Receptor, Adenosine A2A
|keywords=* adenosine
* aging
* apoptosis
* cytokines
* migration
* neutrophils
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680557
}}
{{medline-entry
|title=IFN-γ induces senescence-like characteristics in mouse bone marrow mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28791835
|abstract=Mesenchymal stem cells ([[MSC]]) are considered promising in tissue repair and regeneration medicine due to their proliferation and differentiation ability. Many properties of [[MSC]] are affected by cytokines, and IFN-γ has been shown to regulate [[MSC]] in many aspects. Senescence affects the proliferation, differentiation and cytokine secretion of [[MSC]]. To investigate the effects of IFN-γ on the senescence-associated properties of [[MSC]]. The [[MSC]] used in our study were isolated from the bone marrow (BM) of mice. Cell vitalities were measured by CCK8. The phenotypes and ROS of mBM-[[MSC]] were analyzed by flow cytometry. Cellular senescence was detected using SA-β-gal stains. IL-6 and [[CXCL1]] secretions were measured by ELISA. mBM-[[MSC]] can differentiated into osteocytes and adipocytes. They expressed CD29, CD106, and Sca-1, and did not express CD31, CD45 or FLK1. Our study showed that the cell vitalities of mBM-[[MSC]] were significantly reduced after IFN-γ treatment for 5 days, and the cell numbers were obviously lower after IFN-γ treatment for 5, 10 or 15 days. The IFN-γ group increased SA-β-gal-positive cells and reactive oxygen species (ROS) significantly after 15 days of IFN-γ treatment. Moreover, IL-6 and [[CXCL1]] secretions were upregulated by IFN-γ. Our study shows IFN-γ can induce senescence-like characteristics in mBM-[[MSC]], suggesting a novel target for anti-aging therapy.
|mesh-terms=* Adipogenesis
* Animals
* Bone Marrow Cells
* Cell Differentiation
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Chemokine CXCL1
* Dose-Response Relationship, Drug
* Enzyme-Linked Immunosorbent Assay
* Flow Cytometry
* Interferon-gamma
* Interleukin-6
* Mesenchymal Stem Cells
* Mice
* Osteogenesis
* Reactive Oxygen Species
* Up-Regulation
|keywords=* IFN-γ
* mesenchymal stem cells
* senescence
|full-text-url=https://sci-hub.do/10.17219/acem/61431
}}
{{medline-entry
|title=Methyl caffeate and some plant constituents inhibit age-related inflammation: effects on senescence-associated secretory phenotype (SASP) formation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28299617
|abstract=During aging, cells secrete molecules called senescence-associated secretory phenotype (SASP). They constitute chronic low-grade inflammation environment to adjacent cells and tissues. In order to find inhibiting agents of SASP formation, 113 plant constituents were incubated with BJ fibroblasts for 6 days after treatment with bleomycin. Several plant constituents showed considerable inhibition of IL-6 production, a representative SASP marker. These plant constituents included anthraquinones such as aurantio-obtusin, flavonoids including astragalin, iristectorigenin A, iristectorigenin B, linarin, lignans including lariciresinol 9-O-glucoside and eleutheroside E, phenylpropanoids such as caffeic acid and methyl caffeate, steroid (ophiopogonin), and others like centauroside, rhoifolin and scoparone. In particular, methyl caffeate down-regulated SASP factors such as IL-1α, IL-1β, IL-6, IL-8, GM-CSF, [[CXCL1]], MCP-2, and MMP-3. Inhibition of these SASP mRNA expression levels also coincided with the reduction of IκBζ expression and NF-κB p65 activation without affecting the expression levels of senescence markers, p21 or pRb. Taken together, the present study demonstrated that methyl caffeate might be a specific and strong inhibitor of SASP production without affecting the aging process. Its action mechanisms involve the reduction of IκBζ expression and NF-κB p65 activation. Therefore, this compound might be effective in alleviating chronic low-grade inflammation linked to age-related degenerative disorders.
|mesh-terms=* Caffeic Acids
* Cell Line
* Cellular Senescence
* Dose-Response Relationship, Drug
* Humans
* Inflammation
* Molecular Structure
* Phenotype
* Structure-Activity Relationship
|keywords=* Chronic low-grade inflammation
* IκBζ
* Methyl caffeate
* SASP
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s12272-017-0909-y
}}
{{medline-entry
|title=Adiponectin induces [[CXCL1]] secretion from cancer cells and promotes tumor angiogenesis by inducing stromal fibroblast senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27092462
|abstract=Adiponectin is an adipocyte-specific adipocytokine with proliferative and pro-angiogenic effects that regulates many biological processes, including immunity, insulin resistance, and inflammation. The oncogenic role of adiponectin has been implicated in several cancer types. Stromal cells within tumor contribute tumor growth and angiogenesis; however, it is not clear that how adiponectin regulates stromal cell-mediated tumorigenesis. In this study, using the tumor xenograft models, we demonstrated that tumor development was severely impaired in mouse subcutaneous cancer tissue and metastasis tumor tissue in adiponectin knockout mice. Our results indicated adiponectin deficiency resulted in decrease of blood vessel and stromal senescent fibroblasts in subcutaneous and metastasis tumor tissue. These observations were confirmed in vitro, in which co-cultured tumor cells and fibroblasts treated with adiponectin promoted ECs tube formation. A secretion of [[CXCL1]] by adiponectin-treated tumor cells was observed during the process of inducing stromal fibroblast senescence. Furthermore, stromal cells senescence was through p53 and p16 pathways. Taken together, our results indicate that adiponectin promotes stromal cell senescence within invasive colon cancer contributing to angiogenesis and tumor growth in part through the production of [[CXCL1]] and may serve as a therapeutic target for tumor patients. © 2015 Wiley Periodicals, Inc.
|mesh-terms=* Adiponectin
* Animals
* Cell Line, Tumor
* Chemokine CXCL1
* Coculture Techniques
* Fibroblasts
* Humans
* Mice
* Neoplasm Metastasis
* Neoplasms, Experimental
* Neovascularization, Pathologic
* Signal Transduction
* Stromal Cells
|keywords=* CXCL1
* adiponectin
* senescence
* stromal cells
* tumor angiogenesis
|full-text-url=https://sci-hub.do/10.1002/mc.22428
}}
{{medline-entry
|title=Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26433963
|abstract=It is believed that senescent cells contribute to the progression of primary and metastatic tumors, however, the exact mechanisms of this activity remain elusive. In this report we show that senescent human peritoneal mesothelial cells (HPMCs) alter the secretory profile of ovarian cancer cells (A2780, OVCAR-3, SKOV-3) by increasing the release of four angiogenic agents: [[CXCL1]], [[CXCL8]], [[HGF]], and VEGF. Proliferation and migration of endothelial cells subjected to conditioned medium generated by: cancer cells modified by senescent HPMCs; cancer cells co-cultured with senescent HPMCs; and by early-passage HPMCs from aged donors, were markedly intensified. The same was the case for the vascularization, size and number of tumors that developed in the mouse peritoneum upon injection of ovarian cancer cells with senescent HPMCs. When the identified pro-angiogenic proteins were neutralized in conditioned medium from the cancer cells, both aspects of endothelial cell behavior intensified in vitro in response to senescent HPMCs were markedly reduced. The search for mediators of senescent HPMC activity using specific neutralizing antibodies and recombinant exogenous proteins showed that the intensified angiogenic potential of cancer cells was elicited by IL-6 and TGF-β1. At the transcriptional level, increased proliferation and migration of endothelial cells exposed to cancer cells modified by senescent HPMCs was regulated by HIF-1α, NF-κB/p50 and AP-1/c-Jun. Collectively, our findings indicate that senescent HPMCs may promote the progression of ovarian cancer cells by reprogramming their secretory phenotype towards increased production of pro-angiogenic agents and subsequent increase in the angiogenic capabilities of the vascular endothelium. 
|mesh-terms=* Animals
* Cell Movement
* Cell Proliferation
* Cellular Senescence
* Disease Progression
* Epithelium
* Female
* Heterografts
* Humans
* Mice
* Mice, SCID
* Neovascularization, Pathologic
* Ovarian Neoplasms
* Peritoneum
* Phenotype
|keywords=* Angiogenesis
* Cellular senescence
* Mesothelial cells
* Ovarian cancer
* Peritoneal cavity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740564
}}
{{medline-entry
|title=[[CXCL1]] Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26401931
|abstract=Truncation of tau protein is considered an early event in Alzheimer's disease (AD) and is believed to play a major pathogenic role in sporadic AD. However, causative factors that trigger tau truncation in AD remain poorly understood. In the present study, we demonstrate that [[CXCL1]] (C-X-C motif ligand 1), a specific ligand for the chemokine receptor [[CXCR2]], induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term but not short-term cultured neurons. The cleaved tau formed varicosities or bead-like structures along the neurites, an abnormal distribution of tau induced by [[CXCL1]] that has not been observed previously. [[CXCL1]]-induced activation of GSK3β and the subsequent phosphorylation of tau preceded and were required for caspase-3 activation and tau cleavage. Moreover, intrahippocampal microinjection of lentiviral [[CXCL1]] induced tau cleavage in hippocampal neurons in aged (15-18 months of age) but not adult mice (5-10 months of age). Our data highlight a new role of [[CXCR2]] in tau cleavage and suggest that targeting [[CXCR2]] may offer therapeutic benefits to patients with AD and potentially other tauopathies. 
|mesh-terms=* Aging
* Animals
* Caspase 3
* Cells, Cultured
* Chemokine CXCL1
* Embryo, Mammalian
* Female
* Hippocampus
* Mice
* Mice, Inbred C57BL
* Microinjections
* Microtubule-Associated Proteins
* Mutation
* Neurons
* Pregnancy
* Rats
* Rats, Sprague-Dawley
* Time Factors
* Transfection
* tau Proteins
|keywords=* CXCL1
* CXCR2
* Caspase-3
* hippocampal neurons
* tau cleavage
|full-text-url=https://sci-hub.do/10.3233/JAD-150041
}}
{{medline-entry
|title=Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26093063
|abstract=During senescence, cells express molecules called senescence-associated secretory phenotype (SASP), including growth factors, proinflammatory cytokines, chemokines, and proteases. The SASP induces a chronic low-grade inflammation adjacent to cells and tissues, leading to degenerative diseases. The anti-inflammatory activity of flavonoids was investigated on SASP expression in senescent fibroblasts. Effects of flavonoids on SASP expression such as IL-1α, IL-1β, IL-6, IL-8, GM-CSF, [[CXCL1]], MCP-2 and MMP-3 and signaling molecules were examined in bleomycin-induced senescent BJ cells. In vivo activity of apigenin on SASP suppression was identified in the kidney of aged rats. Among the five naturally-occurring flavonoids initially tested, apigenin and kaempferol strongly inhibited the expression of SASP. These flavonoids inhibited NF-κB p65 activity via the IRAK1/IκBα signaling pathway and expression of IκBζ. Blocking IκBζ expression especially reduced the expression of SASP. A structure-activity relationship study using some synthetic flavones demonstrated that hydroxyl substitutions at C-2',3',4',5 and 7 were important in inhibiting SASP production. Finally, these results were verified by results showing that the oral administration of apigenin significantly reduced elevated levels of SASP and IκBζ mRNA in the kidneys of aged rats. This study is the first to show that certain flavonoids are inhibitors of SASP production, partially related to NF-κB p65 and IκBζ signaling pathway, and may effectively protect or alleviate chronic low-grade inflammation in degenerative diseases such as cardiovascular diseases and late-stage cancer. 
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Bleomycin
* Cell Line
* Cellular Senescence
* Chemokine CCL8
* Chemokine CXCL1
* Fibroblasts
* Flavonoids
* Granulocyte-Macrophage Colony-Stimulating Factor
* Humans
* I-kappa B Proteins
* Interleukins
* Kidney
* Male
* Matrix Metalloproteinase 3
* Nuclear Proteins
* Rats, Sprague-Dawley
* Structure-Activity Relationship
|keywords=* Chronic low-grade inflammation
* Flavonoid
* IκBζ
* SASP
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.bcp.2015.06.013
}}
{{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=Mice with heterozygous deficiency of manganese superoxide dismutase ([[SOD2]]) have a skin immune system with features of "inflamm-aging".
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23856836
|abstract=Dendritic cells (DC) are central in regulating skin immunity. Immunosenescence is associated with a chronic inflammatory state. Little is known about the contribution of DC to "inflamm-aging". When determining langerhans cell (LC) numbers, we found a 60 % reduction of LC in aged epidermis. Reactive oxygen species(ROS) are linked with aging. The mitochondrial manganese superoxide dismutase ([[SOD2]]) is in the first line of antioxidant defense. We investigated the function of DC from [[SOD2]] heterozygous mice ([[SOD2]] /-) and found that at 4 months of age LC numbers are not altered, but activated LC have impaired expression of MHC-II and [[CD44]]. Immature [[SOD2]] /- DC produced increased proinflammatory IL-6 and chemokines [[CXCL1]] and [[CXCL2]]. Upon challenge [[SOD2]] /- DC accumulated ROS. When activating [[SOD2]] /- DC by LPS they less efficiently upregulated MHC-II, [[CD86]] and [[CD44]]. Surprisingly, in vivo contact hypersensitivity (CHS) was enhanced in [[SOD2]] /- mice although [[SOD2]] /- DC were less potent in stimulating wt T cells. However, [[SOD2]] /- T cells showed increased proliferation, even when stimulated with [[SOD2]] /- DC, possibly explaining the increased CHS. Our findings suggest that [[SOD2]] is a molecular candidate in the regulation of "inflamm-aging" conveying both immunosuppressive and proinflammatory signals through alteration of DC and T cell functions.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Animals
* B7-2 Antigen
* Cell Differentiation
* Cells, Cultured
* Chemokine CXCL1
* Chemokine CXCL2
* Dendritic Cells
* Dermatitis, Contact
* Heterozygote
* Histocompatibility Antigens Class II
* Humans
* Hyaluronan Receptors
* Inflammation
* Interleukin-6
* Lymphocyte Activation
* Mice
* Mice, Inbred C57BL
* Mice, Mutant Strains
* Reactive Oxygen Species
* Superoxide Dismutase
* T-Lymphocytes
* Young Adult

|full-text-url=https://sci-hub.do/10.1007/s00403-013-1389-7
}}
{{medline-entry
|title=Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22844481
|abstract=Elderly humans show increased susceptibility to invasive staphylococcal disease after skin and soft tissue infection. However, it is not understood how host immunity changes with aging, and how that predisposes to invasive disease. In a model of severe skin infection, we showed that aged mice (16- to 20-month-old) exhibit dramatic bacterial dissemination compared with young adult mice (2-month-old). Bacterial dissemination was associated with significant reductions of [[CXCL1]] (KC), polymorphonuclear cells (PMNs), and extracellular DNA traps (NETs) at the infection site. PMNs and primary skin fibroblasts isolated from aged mice showed decreased secretion of [[CXCL2]] (MIP-2) and KC in response to MRSA, and in vitro analyses of mitochondrial functions revealed that the mitochondrial electron transport chain complex I plays a significant role in induction of chemokines in the cells isolated from young but not old mice. Additionally, PMNs isolated from aged mice have reduced ability to form NETs and to kill MRSA. Expression of nuclease by S. aureus led to increased bacterial systemic dissemination in young but not old mice, suggesting that defective NETs formation in elderly mice permitted nuclease and non-nuclease expressing S. aureus to disseminate equally well. Overall, these findings suggest that gross impairment of both skin barrier function and innate immunity contributes to the propensity for MRSA to disseminate in aged mice. Furthermore, the study indicates that contribution of bacterial factors to pathogenicity may vary with host age.
|mesh-terms=* Aging
* Animals
* Chemokines
* Deoxyribonucleases
* Electron Transport Complex I
* Extracellular Space
* Female
* Immunity, Innate
* Male
* Methicillin-Resistant Staphylococcus aureus
* Mice
* Neutrophils
* Virulence Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406035
}}
{{medline-entry
|title=Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21604270
|abstract=Previous experimental and clinical studies have suggested that the behavioral and pathological outcomes of spinal cord injury (SCI) are affected by the individual's age at the time of injury. However, the underlying mechanism responsible for these differences remains elusive because it is difficult to match injuries of similar severities between young and adult animals due to differences in the sizes of their respective spinal cords. In this study, the spinal cord size-matched young (4-week-old) and adult (10-week-old) mice were compared to evaluate their locomotor functions and inflammatory cellular/molecular responses after standardized contusion SCI. During the acute phase of SCI, young mice showed better functional recovery and lower pro-inflammatory cytokines/chemokines compared to adult mice. Flow-cytometric analysis revealed that the time courses of leukocyte infiltration were comparable between both groups, while the number of infiltrating neutrophils significantly decreased from 6 h after SCI in young mice. By combining flow-cytometric isolation and gene expression analysis of each inflammatory cell fraction, we found that microglial cells immediately initiate the production of several cytokines in response to SCI, which serve as major sources of IL-6, TNFa, and [[CXCL1]] in injured spinal cord. Interestingly, the secretion of pro-inflammatory cytokines/chemokines but not anti-inflammatory cytokines by microglia was significantly lower in young mice compared to that in adult mice at 3 h after SCI, which will be attributed to the attenuation of the subsequent neutrophil infiltration. These results highlight age-related differences in pro-inflammatory properties of microglial cells that contribute to the amplification of detrimental inflammatory responses after SCI.
|mesh-terms=* Aging
* Animals
* Base Sequence
* Chemokines
* Cytokines
* DNA Primers
* Female
* Gene Expression
* Immunity, Innate
* Inflammation Mediators
* Mice
* Mice, Inbred C57BL
* Microglia
* Neutrophils
* Spinal Cord Injuries

|full-text-url=https://sci-hub.do/10.1002/jcp.22845
}}
{{medline-entry
|title=Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18258444
|abstract=Exercise is a treatment paradigm that can ameliorate cognitive dysfunction in Alzheimer disease (AD) and AD mouse models. Since exercise is also known to alter the peripheral immune response, one potential mechanism for the cognitive improvement following exercise may be by modulating the inflammatory repertoire in the central nervous system. We investigated the effects of voluntary exercise in the Tg2576 mouse model of AD at a time-point at which pathology has already developed. Inflammatory mRNA markers are increased in sedentary Tg2576 mice versus non-transgenic controls. We demonstrate that short-term voluntary wheel running improved spatial learning in aged transgenic mice as compared to sedentary Tg2576 controls. Inflammatory profiles of the Tg2576 and non-transgenic mice were different following exercise with the non-transgenic mice showing a broader response as compared to the Tg2576. Notably, exercising Tg2576 exhibited increases in a few markers including [[CXCL1]] and [[CXCL1]]2, two chemokines that may affect cognition.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Behavior, Animal
* Chemokine CXCL1
* Chemokine CXCL2
* Cognition
* Disease Models, Animal
* Enzyme-Linked Immunosorbent Assay
* Gene Expression Regulation
* Inflammation
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microarray Analysis
* RNA, Messenger
* Time Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386749
}}
{{medline-entry
|title=Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17601796
|abstract=Adenosine is generated at sites of tissue injury where it serves to regulate inflammation and damage. Adenosine signaling has been implicated in the regulation of pulmonary inflammation and damage in diseases such as asthma and chronic obstructive pulmonary disease; however, the contribution of specific adenosine receptors to key immunoregulatory processes in these diseases is still unclear. Mice deficient in the purine catabolic enzyme adenosine deaminase ([[ADA]]) develop pulmonary inflammation and mucous metaplasia in association with adenosine elevations making them a useful model for assessing the contribution of specific adenosine receptors to adenosine-mediated pulmonary disease. Studies suggest that the A(2A) adenosine receptor (A(2A)R) functions to limit inflammation and promote tissue protection; however, the contribution of A(2A)R signaling has not been examined in the [[ADA]]-deficient model of adenosine-mediated lung inflammation. The purpose of the current study was to examine the contribution of A(2A)R signaling to the pulmonary phenotype seen in [[ADA]]-deficient mice. This was accomplished by generating [[ADA]]/A(2A)R double knockout mice. Genetic removal of the A(2A)R from [[ADA]]-deficient mice resulted in enhanced inflammation comprised largely of macrophages and neutrophils, mucin production in the bronchial airways, and angiogenesis, relative to that seen in the lungs of [[ADA]]-deficient mice with the A(2A)R. In addition, levels of the chemokines monocyte chemoattractant protein-1 and [[CXCL1]] were elevated, whereas levels of cytokines such as [[TNF]]-alpha and IL-6 were not. There were no compensatory changes in the other adenosine receptors in the lungs of [[ADA]]/A(2A)R double knockout mice. These findings suggest that the A(2A)R plays a protective role in the [[ADA]]-deficient model of pulmonary inflammation.
|mesh-terms=* Adenosine Deaminase
* Animals
* Bronchoalveolar Lavage Fluid
* Cell Count
* Chemokines
* Gene Expression Regulation
* Inflammation Mediators
* Longevity
* Lung
* Mice
* Mice, Inbred Strains
* Mice, Knockout
* Mucins
* Mucus
* Neovascularization, Pathologic
* Pneumonia
* RNA, Messenger
* Receptor, Adenosine A2A
* Receptors, Interleukin-8B
* Trachea

|full-text-url=https://sci-hub.do/10.1152/ajplung.00187.2007
}}
{{medline-entry
|title=Age-associated alterations in [[CXCL1]] chemokine expression by murine B cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15274748
|abstract=The [[CXCL1]] chemokines, macrophage inflammatory protein-2 ([[MIP]]-2) and cytokine-induced neutrophil chemoattractant (KC), have been shown to play a role in a number of pathophysiological disease states including endotoxin-induced inflammation and bacterial meningitis. While the expression of these chemokines has been identified in a variety of cell types in the mouse, little is known about their expression with murine B-lymphocytes. Here, we demonstrate that highly purified murine splenic B cells are capable of expressing both [[MIP]]-2 and KC protein and mRNA upon activation with lipopolysaccharide (LPS) but not in response to anti-micro and anti-[[CD40]] in combination with interleukin-4 (IL-4) stimulation. Moreover, these chemokines are expressed at higher levels in B cells derived from young (4 m) compared to old (24-29 m) mice. Upon fractionation into distinct B-cell subsets, we found that the expression of [[MIP]]-2 and KC by aged follicular (FO) B cells is significantly decreased when compared to the same cells from younger mice, while only [[MIP]]-2 production was found to be diminished in aged marginal zone (MZ) B cells. Interestingly, [[MIP]]-2 and KC production by newly formed (NF) B cells did not significantly differ with age. Moreover, the potential relevance of these findings is supported by the poor ability of LPS-activated aged B cells to specifically mediate [[CXCL1]]-dependent leukocyte recruitment when compared to younger B cells. Overall, the decreased expression of [[CXCL1]] chemokines by aged B cells in response to LPS may have potential implications on the secondary recruitment of leukocytes to sites of microbial infections and inflammation possibly contributing to the increased susceptibility of older subjects to pathogen challenge.
|mesh-terms=* Aging
* Animals
* Antibodies, Anti-Idiotypic
* Antibodies, Monoclonal
* B-Lymphocyte Subsets
* B-Lymphocytes
* CD40 Antigens
* Cells, Cultured
* Chemokine CXCL1
* Chemokine CXCL2
* Chemokines
* Chemokines, CXC
* Immunoglobulin M
* Intercellular Signaling Peptides and Proteins
* Lipopolysaccharides
* Mice
* Mice, Inbred C57BL
* Specific Pathogen-Free Organisms
* Spleen

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC509242
}}