C-C chemokine receptor type 2 (C-C CKR-2) (CC-CKR-2) (CCR-2) (CCR2) (Monocyte chemoattractant protein 1 receptor) (MCP-1-R) (CD192 antigen) [CMKBR2]

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Hip Fracture Leads to Transitory Immune Imprint in Older Patients.

Hip fracture (HF) is common in the geriatric population and is associated with a poor vital and functional prognosis which could be impacted by immunological changes. The objective here is to decipher immune changes occurring in the 1st days following HF and determine how phenotype, function, and regulation of innate and adaptive compartments adapt during acute stress event. We included HF patients, aged over 75 years. For each patient, blood samples were taken at five different timepoints: four in the perioperative period (day 0 to hospital discharge) and one at long term (6-12 months). Phenotypical and functional analysis were performed longitudinally on fresh blood or cryopreserved PBMCs. Clinical data were prospectively collected. One-hundred HF patients and 60 age-matched controls were included. Innate compartment exhibits pro-inflammatory phenotypes (hyperleukocytosis, increase of CD14 CD16 proportion and CCR2 expression), maintaining its ability to produce pro-inflammatory cytokines. Adaptive compartment extends toward a transitory immunosuppressive profile (leucopenia) associated with an active T-cell proliferation. Furthermore, increases of LAG-3 and PD-1 and a decrease of 2-B4 expression are observed on T-cells, reinforcing their transitory suppressive status. Of note, these immune changes are transitory and sequential but may participate to a regulation loop necessary for homeostatic immune control at long term. HF is associated with several transitory immunological changes including pro-inflammatory phenotype in innate compartment and immunosuppressive profile in adaptive compartment. A comprehensive assessment of immune mechanisms implicated in the patient's prognosis after HF could pave the way to develop new immune therapeutics strategies.


Keywords

  • acute stress
  • aging
  • immune response
  • inflammation
  • regulation loop


The CC-chemokine receptor 2 is involved in the control of ovarian folliculogenesis and fertility lifespan in mice.

The chemokine receptor 2 (CCR2) was first described as a chemotactic factor involved in immune responses, but it also plays an essential function in several biological processes. The chemokine (C-C motif) ligand 2 (CCL2) binds to CCR2 triggering G protein-coupled receptor (GPCR) signaling in leukocytes, including activation of PI3K/Akt/mTOR, a key pathway that is also related to follicular activation and survival. However, the potential role of CCR2 in ovarian follicular physiology remain unexplored. Thus, we investigated the role of CCR2 on follicular growth during adult life and aging. Ovaries and oocytes were collected from wild type (WT) mice at 1.5 months old (mo), and CCR2 expression was observed predominantly in oocytes included in growing follicles, as well as after ovulation. Follicle populations were assessed in WT and CCR2-/- mice at 1.5 mo, and CCR2-/- mice had more primordial and less primary and secondary follicles, while there were no differences in antral follicle numbers. Pro-apoptotic genes Bax and Casp3 were downregulated, while anti-apoptotic Bcl2 was upregulated in CCR2-/- mice. To further characterize the role of CCR2 in ovarian aging, follicle populations were assessed in WT and CCR2-/- mice at 1.5, 2.5, 6, 10, and 12 mo. A larger ovarian follicular reserve at 1.5-6 mo was observed in CCR2-/- mice. Finally, CCR2-/- aged mice (6-12 mo) ovulated more oocytes than WT mice. Altogether, these data suggest that CCR2 plays an important role in the regulation of murine folliculogenesis, potentially affecting the reproductive lifespan.


Keywords

  • Aging
  • CCR2
  • Fertility
  • Follicle
  • Ovary


Deficit of resolution receptor magnifies inflammatory leukocyte directed cardiorenal and endothelial dysfunction with signs of cardiomyopathy of obesity.

Chronic unresolved inflammation is the primary determinant of cardiovascular disease. Precise mechanisms that define the genesis of unresolved inflammation in heart failure with preserved ejection fraction (HFpEF) are of interest due to the obesity epidemic. To examine the obesity phenotype and its direct/indirect consequences, multiple approaches were employed using the lipoxin receptor (abbreviated as ALX) dysfunction mouse model. Indirect calorimetry analyses revealed that the deletion of ALX dysregulated energy metabolism driving toward age-related obesity. Heart function data suggest that obesity-prone ALX deficient mice had impaired myocardium strain. Comprehensive measurement of chemokines, extracellular matrix, and arrhythmogenic arrays confirmed the dysregulation of multiple ion channels gene expression with amplified inflammatory chemokines and cytokines response at the age of 4 months compared with WT counterparts. Quantitative analyses of leukocytes demonstrated an increase of proinflammatory Ly6C CCR2 macrophages in the spleen and heart at a steady-state resulting in an inflamed splenocardiac axis. Signs of subtle inflammation were marked with cardiorenal, endothelial defects with decreased CD31 and eNOS and an increased iNOS and COX2 expression. Thus, ALX receptor deficiency serves as an experimental model that defines multiple cellular and molecular mechanisms in HFpEF that could be a target for the development of HFpEF therapy in cardiovascular medicine.


Keywords

  • inflammatory macrophage
  • kidney function
  • non-resolving inflammation
  • obesogenic aging


Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.

Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2 myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.


Keywords

  • Aging
  • Bone marrow transplantation
  • Cardiology
  • Hematopoietic stem cells
  • Macrophages


Inflammation and Ectopic Fat Deposition in the Aging Murine Liver Is Influenced by CCR2.

Aging is associated with inflammation and metabolic syndrome, which manifests in the liver as nonalcoholic fatty liver disease (NAFLD). NAFLD can range in severity from steatosis to fibrotic steatohepatitis and is a major cause of hepatic morbidity. However, the pathogenesis of NAFLD in naturally aged animals is unclear. Herein, we performed a comprehensive study of lipid content and inflammatory signature of livers in 19-month-old aged female mice. These animals exhibited increased body and liver weight, hepatic triglycerides, and inflammatory gene expression compared with 3-month-old young controls. The aged mice also had a significant increase in F4/80 hepatic macrophages, which coexpressed CD11b, suggesting a circulating monocyte origin. A global knockout of the receptor for monocyte chemoattractant protein (CCR2) prevented excess steatosis and inflammation in aging livers but did not reduce the number of CD11b macrophages, suggesting changes in macrophage accumulation precede or are independent from chemokine (C-C motif) ligand-CCR2 signaling in the development of age-related NAFLD. RNA sequencing further elucidated complex changes in inflammatory and metabolic gene expression in the aging liver. In conclusion, we report a previously unknown accumulation of CD11b macrophages in aged livers with robust inflammatory and metabolic transcriptomic changes. A better understanding of the hallmarks of aging in the liver will be crucial in the development of preventive measures and treatments for end-stage liver disease in elderly patients.

MeSH Terms

  • Aging
  • Animals
  • Body Weight
  • Chemokine CCL2
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Inflammation
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease
  • Organ Size
  • Receptors, CCR2


Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.

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


Aging induces cardiac mesenchymal stromal cell senescence and promotes endothelial cell fate of the CD90   subset.

Aging is a major risk factor in the development of chronic diseases, especially cardiovascular diseases. Age-related organ dysfunction is strongly associated with the accumulation of senescent cells. Cardiac mesenchymal stromal cells (cMSCs), deemed part of the microenvironment, modulate cardiac homeostasis through their vascular differentiation potential and paracrine activity. Transcriptomic analysis of cMSCs identified age-dependent biological pathways regulating immune responses and angiogenesis. Aged cMSCs displayed a senescence program characterized by Cdkn2a expression, decreased proliferation and clonogenicity, and acquisition of a senescence-associated secretory phenotype (SASP). Increased CCR2-dependent monocyte recruitment by aged cMSCs was associated with increased IL-1ß production by inflammatory macrophages in the aging heart. In turn, IL-1ß induced senescence in cMSCs and mimicked age-related phenotypic changes such as decreased CD90 expression. The CD90  and CD90- cMSC subsets had biased vascular differentiation potentials, and CD90  cMSCs were more prone to acquire markers of the endothelial lineage with aging. These features were related to the emergence of a new cMSC subset in the aging heart, expressing CD31 and endothelial genes. These results demonstrate that cMSC senescence and SASP production are supported by the installation of an inflammatory amplification loop, which could sustain cMSC senescence and interfere with their vascular differentiation potentials.

MeSH Terms

  • Aging
  • Animals
  • Cell Differentiation
  • Cellular Senescence
  • Endothelial Cells
  • Humans
  • Interferon-beta
  • Interleukin-1beta
  • Mesenchymal Stem Cells
  • Mice
  • Myocardium
  • Thy-1 Antigens

Keywords

  • CD90
  • IL-1ß
  • heart
  • macrophages
  • mesenchymal stromal cells
  • senescence


Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.

Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium [i]Akkermansia muciniphila[/i] impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2 monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2 monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either [i]A. muciniphila[/i] or the antibiotic enrofloxacin, which increased the abundance of [i]A. muciniphila[/i], restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2 monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte-B cell axis could potentially be targeted to reverse age-associated IR.

MeSH Terms

  • Aging
  • Animals
  • Bacteria
  • Butyrates
  • Cell Line
  • Dysbiosis
  • Enrofloxacin
  • Female
  • Gastrointestinal Microbiome
  • Immunity, Innate
  • Insulin Resistance
  • Macaca
  • Mice, Inbred C57BL
  • Monocytes
  • Omentum
  • Receptors, CCR2


Persistent Infiltration and Impaired Response of Peripherally-Derived Monocytes after Traumatic Brain Injury in the Aged Brain.

Traumatic brain injury (TBI) is a leading cause for neurological disabilities world-wide. TBI occurs most frequently among the elderly population, and elderly TBI survivors suffer from reduced recovery and poorer quality of life. The effect of age on the pathophysiology of TBI is still poorly understood. We previously established that peripherally-derived monocytes (CCR2⁺) infiltrate the injured brain and contribute to chronic TBI-induced cognitive deficits in young animals. Furthermore, age was shown to amplify monocyte infiltration acutely after injury. In the current study, we investigated the impact of age on the subchronic response of peripherally-derived monocytes (CD45 ; CCR2⁺) and their role in the development of chronic cognitive deficits. In the aged brain, there was a significant increase in the number of peripherally-derived monocytes after injury compared to young, injured animals. The infiltration rate of peripherally-derived monocytes remained elevated subchronically and corresponded with enhanced expression of CCR2 chemotactic ligands. Interestingly, the myeloid cell populations observed in injured aged brains had impaired anti-inflammatory responses compared to those in young animals. Additionally, in the aged animals, there was an expansion of the blood CCR2⁺ monocyte population after injury that was not present in the young animals. Importantly, knocking out CCR2 to inhibit infiltration of peripherally-derived monocytes prevented chronic TBI-induced spatial memory deficits in the aged mice. Altogether, these results demonstrate the critical effects of age on the peripherally-derived monocyte response during the progression of TBI pathophysiology.

MeSH Terms

  • Aging
  • Animals
  • Brain
  • Brain Injuries, Traumatic
  • Cognition
  • Disease Models, Animal
  • Flow Cytometry
  • Inflammation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes
  • Receptors, CCR2

Keywords

  • ageing
  • cognition
  • inflammation
  • monocyte
  • traumatic brain injury


Cryopreserved whole blood for the quantification of monocyte, T-cell and NK-cell subsets, and monocyte receptor expression by multi-color flow cytometry: A methodological study based on participants from the canadian longitudinal study on aging.

Immunophenotyping by multi-color flow cytometry is arguably the best tool to identify and quantify distinct cell lineages from the peripheral blood and other biological fluids/tissues. Effective in both clinical and research settings, it can be used to estimate the frequency of a given cell type or measure its phenotypic or functional properties. Normally, immunophenotyping is performed in fresh or fractionated blood (i.e., PBMCs) the same day, or within 24 hours of collection; however, this may not be feasible for all study designs. We have previously shown that cryopreserved blood, a biospecimen that is simple and inexpensive to prepare, is comparable to fresh blood for the enumeration of major leukocyte cell types. For the following study, we sought to extend these observations to distinct subsets of: monocytes (classical, intermediate, and non-classical), T-cells (CD4/CD8 naïve, central and effector memory, senescent, and terminally differentiated, and regulatory T-cells), and NK-cells (CD56 bright and dim); we also examined the expression of monocyte cell-surface receptors CX3CR1, CCR2, TLR2, and TLR4. Our results indicate that cryopreserved blood is comparable to fresh blood; with exception to relatively rare subsets and lowly expressed receptors, the absolute or relative frequency of cell subsets generally correlated >0.80 between blood types, while monocyte receptor expressed was mostly >0.70. Furthermore, the day-to-day coefficient of variation for most cell subsets and parameters was below 20%. Given these findings, we suggest that cryopreserved peripheral blood be given greater consideration for studies in which the quantification of distinct leukocyte subsets is required. © 2018 International Society for Advancement of Cytometry.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Canada
  • Cryopreservation
  • Female
  • Flow Cytometry
  • Humans
  • Immunophenotyping
  • Killer Cells, Natural
  • Longitudinal Studies
  • Lymphocyte Subsets
  • Male
  • Middle Aged
  • Monocytes
  • T-Lymphocytes

Keywords

  • Canadian Longitudinal Study on Aging (CLSA)
  • T-cells
  • blood
  • flow cytometry
  • immunophenotyping
  • monocytes
  • natural killer cells
  • regulatory T-cells


Inhibition of Radiation-Induced Ccl2 Signaling Protects Lungs from Vascular Dysfunction and Endothelial Cell Loss.

Radiation-induced normal tissue toxicity often precludes the application of curative radiation doses. Here we investigated the therapeutic potential of chemokine C-C motif ligand 2 (Ccl2) signaling inhibition to protect normal lung tissue from radiotherapy (RT)-induced injury. RT-induced vascular dysfunction and associated adverse effects can be efficiently antagonized by inhibition of Ccl2 signaling using either the selective Ccl2 inhibitor bindarit (BIN) or mice deficient for the main Ccl2 receptor CCR2 (KO). BIN-treatment efficiently counteracted the RT-induced expression of Ccl2, normalized endothelial cell (EC) morphology and vascular function, and limited lung inflammation and metastasis early after irradiation (acute effects). A similar protection of the vascular compartment was detected by loss of Ccl2 signaling in lungs of CCR2-KO mice. Long-term Ccl2 signaling inhibition also significantly limited EC loss and accompanied fibrosis progression as adverse late effect. With respect to the human situation, we further confirmed that Ccl2 secreted by RT-induced senescent epithelial cells resulted in the activation of normally quiescent but DNA-damaged EC finally leading to EC loss in [i]ex vivo[/i] cultured human normal lung tissue. Abrogation of certain aspects of the secretome of irradiated resident lung cells, in particular signaling inhibition of the senescence-associated secretory phenotype-factor Ccl2 secreted predominantly by RT-induced senescent epithelial cells, resulted in protection of the endothelial compartment. Radioprotection of the normal tissue [i]via[/i] Ccl2 signaling inhibition without simultaneous protection or preferable radiosensitization of tumor tissue might improve local tumor control and survival, because higher doses of radiation could be used.

MeSH Terms

  • Animals
  • Biomarkers
  • Biopsy
  • Cell Survival
  • Cellular Senescence
  • Chemokine CCL2
  • Disease Models, Animal
  • Endothelial Cells
  • Endothelium, Vascular
  • Humans
  • Lung
  • Lung Neoplasms
  • Mice
  • Mice, Knockout
  • Pneumonia
  • Protective Agents
  • Protein Binding
  • Radiation Injuries
  • Receptors, CCR2
  • Respiratory Mucosa
  • Signal Transduction

Keywords

  • Ccl2
  • radiation-induced normal tissue toxicity
  • radiotherapy
  • senescence
  • vascular damage


Attenuated Macrophage Infiltration in Glomeruli of Aged Mice Resulting in Ameliorated Kidney Injury in Nephrotoxic Serum Nephritis.

Senescent cells have deleterious effects on the tissue microenvironment through proinflammatory senescence-associated secretory phenotypes; meanwhile, the onset of glomerulonephritis is predominant in younger adults. To clarify the influence of aging on the onset and development of glomerulonephritis, we used a murine model of antibody-mediated nephritis. Sheep nephrotoxic serum was administered in C57BL/6J mice at 12 weeks (adult) or 18 months old (aged) after pre-immunization with sheep IgG. Depositions of sheep IgG and autologous mouse IgG along the glomerular basement membrane and the serum titer of anti-sheep IgG-specific mouse IgG were similar between adult and aged mice. However, kidney injury was depressed in aged mice, accompanied by reduced macrophage infiltration in the glomeruli. The mRNA expression of most chemokines involved in monocyte/macrophage chemotaxis was not different between adult and aged mice, but the cell surface expression of C-C chemokine receptor (CCR) 1 and CCR2 was down-regulated in the monocyte/macrophage lineage cells infiltrating the kidneys of aged nephritic mice. Furthermore, expression of all four isotypes of the Fcγ receptor (FcγR) was reduced in these cells. Both CCR and FcγR expression were down-regulated in monocyte/macrophage lineage cells, resulting in attenuated glomerular infiltration of these cells and impaired glomerular injury in aged mice.

MeSH Terms

  • Aging
  • Animals
  • Cellular Microenvironment
  • Chemokines
  • Glomerulonephritis
  • Immunoglobulin G
  • Kidney Glomerulus
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CCR
  • Receptors, IgG
  • Sheep


Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression.

Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2 myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2 myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC.

MeSH Terms

  • Animals
  • Carcinoma, Hepatocellular
  • Cellular Senescence
  • Disease Progression
  • Female
  • Humans
  • Immunologic Surveillance
  • Liver Neoplasms
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout

Keywords

  • CCL2
  • CCR2
  • HCC
  • MDSC
  • NK cells
  • hepatocellular carcinoma
  • liver cancer
  • macrophages
  • myeloid cells
  • senescence


Absence of CCR2 results in an inflammaging environment in young mice with age-independent impairments in muscle regeneration.

Skeletal muscle regeneration requires coordination between dynamic cellular populations and tissue microenvironments. Macrophages, recruited via CCR2, are essential for regeneration; however, the contribution of macrophages and the role of CCR2 on nonhematopoietic cells has not been defined. In addition, aging and sex interactions in regeneration and sarcopenia are unclear. Muscle regeneration was measured in young (3-6 mo), middle (11-15 mo), old (24-32 mo) male and female CCR2 mice. Whereas age-related muscle atrophy/sarcopenia was present, regenerated myofiber cross-sectional area (CSA) in CCR2 mice was comparably impaired across all ages and sexes, with increased adipocyte area compared with wild-type (WT) mice. CCR2 mice myofibers achieved approximately one third of baseline CSA even 84 d after injury. Regenerated CSA and clearance of necrotic tissue were dependent on bone marrow-derived cellular expression of CCR2. Myogenic progenitor cells isolated from WT and CCR2 mice exhibited comparable proliferation and differentiation capacity. The most striking cellular anomaly in injured muscle of CCR2 mice was markedly decreased macrophages, with a predominance of Ly6C anti-inflammatory monocytes/macrophages. Ablation of proinflammatory TLR signaling did not affect muscle regeneration or resolution of necrosis. Of interest, many proinflammatory, proangiogenic, and chemotactic cytokines were markedly elevated in injured muscle of CCR2 relative to WT mice despite impairments in macrophage recruitment. Collectively, these results suggest that CCR2 on bone marrow-derived cells, likely macrophages, were essential to muscle regeneration independent of TLR signaling, aging, and sex. Decreased proinflammatory monocytes/macrophages actually promoted a proinflammatory microenvironment, which suggests that inflammaging was present in young CCR2 mice.

MeSH Terms

  • Adaptor Proteins, Vesicular Transport
  • Aging
  • Animals
  • Body Weight
  • Cell Cycle
  • Cell Division
  • Cytokines
  • Female
  • Inflammation
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes
  • Muscle Development
  • Muscle, Skeletal
  • Myeloid Differentiation Factor 88
  • Myoblasts
  • Myositis
  • Necrosis
  • Radiation Chimera
  • Receptors, CCR2
  • Regeneration
  • Sarcopenia
  • Specific Pathogen-Free Organisms

Keywords

  • TLRs
  • monocytes/macrophages
  • myogenic progenitor cells
  • sarcopenia


Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities.

Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80(hi)GATA6( ) macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C( ) monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80(lo)MHCII( ) cells that act, in part, as precursors of F4/80(hi)GATA6( ) macrophages. Notably, monocyte-derived F4/80(hi) macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.

MeSH Terms

  • Aging
  • Animals
  • Cell Proliferation
  • Cell Self Renewal
  • Embryo, Mammalian
  • Macrophages
  • Mice, Inbred C57BL
  • Myeloid Cells
  • Peritoneum
  • Phenotype
  • Receptors, CCR2
  • Time Factors


Age exacerbates the CCR2/5-mediated neuroinflammatory response to traumatic brain injury.

Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases, including Alzheimer's disease (AD) and numerous recent reports document the development of dementia after TBI. Age is a significant factor in both the risk of and the incidence of acquired brain injury. TBI-induced inflammatory response is associated with activation of brain resident microglia and accumulation of infiltrating monocytes, which plays a pivotal role in chronic neurodegeneration and loss of neurological function after TBI. Despite the extensive clinical evidence implicating neuroinflammation with the TBI-related sequelae, the specific role of these different myeloid cells and the influence of age on TBI-initiated innate immune response remain unknown and poorly studied. We used gene profiling and pathway analysis to define the effect of age on inflammatory response at the time of injury. The recruitment of peripheral CCR2( ) macrophages was delineated using the CX3CR1 (GFP/ ) CCR2 (RFP/ ) reporter mouse. These responses were examined in the context of CCR2/5 antagonism using cenicriviroc. Unsupervised gene clustering and pathway analysis revealed that age predisposes exacerbated inflammatory response related to the recruitment and activation of peripheral monocytes to the injured brain. Using a unique reporter animal model able to discriminate resident versus peripherally derived myeloid cells, we demonstrate that in the aged brain, there is an increased accumulation of peripherally derived CCR2( ) macrophages after TBI compared to young animals. Exaggerated recruitment of this population of cells was associated with an augmented inflammatory response in the aged TBI animals. Targeting this cellular response with cenicriviroc, a dual CCR2/5 antagonist, significantly ameliorated injury-induced sequelae in the aged TBI animals. Importantly, these findings demonstrate that peripheral monocytes play a non-redundant and contributing role to the etiology of trauma-induced inflammatory sequelae in the aged brain.

MeSH Terms

  • Aging
  • Animals
  • Brain Injuries, Traumatic
  • Cluster Analysis
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Inflammation
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Real-Time Polymerase Chain Reaction
  • Receptors, CCR2
  • Receptors, CCR5

Keywords

  • Aging
  • Antagonist
  • CCR2
  • Chemokine
  • Macrophage
  • Microglia
  • Neurotrauma


Enhanced Ccl2-Ccr2 signaling drives more severe choroidal neovascularization with aging.

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


Alterations in Monocyte Phenotypes and Functions after a Hip Fracture in Elderly Individuals: A 6-Month Longitudinal Study.

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


TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity.

Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C monocytes from old (18-22 mo) mice and CD14 CD16 intermediate/inflammatory monocytes from older adults also contributed to this "age-associated inflammation" as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity.

MeSH Terms

  • Aging
  • Animals
  • Female
  • Flow Cytometry
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Monocytes
  • Pneumococcal Infections
  • Streptococcus pneumoniae
  • Tumor Necrosis Factor-alpha


Senescent dermal fibroblasts enhance stem cell migration through CCL2/CCR2 axis.

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


Differential expression of monocyte surface markers among TB patients with diabetes co-morbidity.

The expression of monocyte surface markers was compared between tuberculosis patients with and without type 2 diabetes (DM2). DM2 was associated with increased CCR2 expression, which may restrain monocyte traffic to the lung. Other host factors associated with baseline monocyte changes were older age (associated with lower CD11b) and obesity (associated with higher RAGE). Given that DM2 patients are more likely to be older and obese, their monocytes are predicted to be altered in function in ways that affect their interaction with Mycobacterium tuberculosis.

MeSH Terms

  • Aging
  • Biomarkers
  • Body Mass Index
  • CD11b Antigen
  • Cell Adhesion
  • Comorbidity
  • Diabetes Mellitus, Type 2
  • Disease Susceptibility
  • Female
  • Host-Pathogen Interactions
  • Humans
  • Male
  • Monocytes
  • Mycobacterium tuberculosis
  • Prognosis
  • Receptor for Advanced Glycation End Products
  • Receptors, CCR2
  • Receptors, Cell Surface
  • Tuberculosis

Keywords

  • CCR2
  • CD11b
  • Diabetes
  • Innate immunity
  • Monocyte
  • RAGE
  • Tuberculosis


[[[CCR5]], CCR2, apoe, p53, ITGB3 and HFE gene polymorphism in Western Siberia long-livers].

In order to estimate the distribution of some polymorphisms for the CCR5, CCR2, apoE, p53, ITGB3, and HFE genes in Russian long-livers from Western Siberia, a sample of 271 individuals (range 90-105 years) was examined. It was demonstrated that carriage of the delta32 polymorphism for the CCR5 gene, V64/polymorphism for the CCR2 gene, e2/e3/e4 for the apoE gene, L33P for the ITGB3 gene, as well as H63D and S65C polymorphisms for the HFE gene does not influence on predisposition to the longevity; carriage of the 282 Y allele for the HFE gene negatively influences on the longevity; carriage of the heterozygous genotype for the R72P polymorphism for the p53 gene correlates with the longevity of elderly people.

MeSH Terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Apolipoproteins E
  • DNA
  • Gene Frequency
  • Genes, p53
  • Genotype
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I
  • Humans
  • Integrin beta3
  • Longevity
  • Male
  • Membrane Proteins
  • Middle Aged
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Receptors, CCR5
  • Siberia