Dataset Information

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

ABSTRACT: While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

SUBMITTER: Raghu H

PROVIDER: S-EPMC5834918 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

Raghu Harini H Lepus Christin M CM Wang Qian Q Wong Heidi H HH Lingampalli Nithya N Oliviero Francesca F Punzi Leonardo L Giori Nicholas J NJ Goodman Stuart B SB Chu Constance R CR Sokolove Jeremy B JB Robinson William H WH

Annals of the rheumatic diseases 20161213 5

<h4>Objectives</h4>While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.<h4>Methods</h4><i>Ccl2</i>-, <i>Ccr2</i>-, <i>Ccl5</i>- and <i>Ccr5</i>-deficient and control mice were subjected to destabilisation ...[more]

PMID: 27965260

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Project description:RATIONALE:Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in the context of tissue injury or disease, large numbers of monocytes infiltrate the heart and are thought to contribute to adverse remodeling and heart failure pathogenesis. Little is understood about the diversity of monocytes and monocyte-derived macrophages recruited to the heart after myocardial injury, including the mechanisms that regulate monocyte recruitment and fate specification. OBJECTIVE:We sought to test the hypothesis that distinct subsets of tissue-resident CCR2- (C-C chemokine receptor 2) and CCR2+ macrophages orchestrate monocyte recruitment and fate specification after myocardial injury. METHODS AND RESULTS:We reveal that in numerous mouse models of cardiomyocyte cell death (permanent myocardial infarction, reperfused myocardial infarction, and diphtheria toxin cardiomyocyte ablation), there is a shift in macrophage ontogeny whereby tissue-resident macrophages are predominately replaced by infiltrating monocytes and monocyte-derived macrophages. Using syngeneic cardiac transplantation to model ischemia-reperfusion injury and distinguish tissue-resident from recruited cell populations in combination with intravital 2-photon microscopy, we demonstrate that monocyte recruitment is differentially orchestrated by distinct subsets of tissue-resident cardiac macrophages. Tissue-resident CCR2+ macrophages promote monocyte recruitment through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism that results in release of MCPs (monocyte chemoattractant proteins) and monocyte mobilization. In contrast, tissue-resident CCR2- macrophages inhibit monocyte recruitment. Using CD (cluster of differentiation) 169-DTR (diphtheria toxin receptor) and CCR2-DTR mice, we further show that selective depletion of either tissue-resident CCR2- or CCR2+ macrophages before myocardial infarction results in divergent effects on left ventricular function, myocardial remodeling, and monocyte recruitment. Finally, using single-cell RNA sequencing, we show that tissue-resident cardiac macrophages differentially instruct monocyte fate specification. CONCLUSIONS:Collectively, these observations establish the mechanistic basis by which monocytes are initially recruited to the injured heart and provide new insights into the heterogeneity of monocyte-derived macrophages.

Project description:Background: Age-related macular degeneration (AMD) is the most common cause of progressive and irreversible blindness in developed countries. Although the pathogenesis is not fully understood, AMD is a multifactorial pathology with an accumulation of inflammatory components and macrophages and a strong genetic predisposition. Our purpose was to investigate the association between early AMD and CCL2 (rs1024611, rs4586, rs2857656) and CCR2 (rs1799865) single nucleotide polymorphisms (SNPs) and CCL2, CCR2 serum levels in a Lithuanian population. Methods: The study included 310 patients with early AMD and 384 healthy subjects. Genotyping of CCL2 rs1024611, rs4586, rs2857656, and CCR2 rs1799865 was performed using a real-time polymerase chain reaction method, while CCL2 and CCR2 chemokines serum concentrations were analyzed using an enzyme-linked immunosorbent assay. Results: We found that the G allele at CCL2 rs1024611 was more prevalent in the early AMD group than in controls (29.2% vs. 24.1%, p = 0.032). Similarly, the C allele in CCL2 rs2857656 is more common in the early AMD group than in controls (29.2% vs. 24.2%, p = 0.037). Binomial logistic regression revealed that each G allele in rs1024611 was associated with 1.3-fold increased odds of developing early AMD under the additive model (OR = 1.322; 95% CI: 1.032–1.697, p = 0.027) as was each C allele in rs2857656 under the additive model (OR = 1.314; 95% CI: 1.025–1.684, p = 0.031). Haplotype analysis revealed that the C-A-G haplotype of CCL2 SNPs was associated with 35% decreased odds of early AMD development. Further analysis showed elevated CCL2 serum levels in the group with early AMD compared to controls (median (IQR): 1181.6 (522.6) pg/mL vs. 879.9 (494.4) pg/mL, p = 0.013); however, there were no differences between CCR2 serum levels within groups. Conclusions: We found the associations between minor alleles at CCL2 rs1024611 and rs2857656, elevated CCL2 serum levels, and early AMD development.

Dataset Information

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

Publications

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

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