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Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure.

ABSTRACT: Ozone-induced lung injury is associated with an accumulation of activated macrophages in the lung. Chemokine receptor CCR2 mediates the migration of inflammatory monocytes/macrophages to sites of tissue injury. It is also required for monocyte egress from the bone marrow. In the present studies, we analyzed the role of CCR2 in inflammatory cell trafficking to the lung in response to ozone. Treatment of mice with ozone (0.8?ppm, 3?h) resulted in increases in proinflammatory CCR2⁺ macrophages in the lung at 24?h, as well as proinflammatory CD11b?⁺?Ly6C^Hi and iNOS⁺?macrophages at 24 and 48?h. Mannose receptor⁺?anti-inflammatory macrophages were also observed in the lung 24 and 48?h post-ozone. Loss of CCR2 was associated with reduced numbers of proinflammatory macrophages in the lung and decreased expression of the proinflammatory cytokines, IL-1? and TNF?. Decreases in anti-inflammatory CD11b?⁺?Ly6C^Lo macrophages were also observed in lungs of CCR2^-/- mice treated with ozone, whereas mannose receptor^+?macrophage accumulation was delayed; conversely, CX3CL1 and CX3CR1 were upregulated. Changes in lung macrophage subpopulations and inflammatory gene expression in CCR2^-/- mice were correlated with reduced ozone toxicity and oxidative stress, as measured by decreases in bronchoalveolar lavage protein content and reduced lung expression of heme-oxygenase-1, 4-hydroxynonenal and cytochrome b5. These data demonstrate that CCR2 plays a role in both pro- and anti-inflammatory macrophage accumulation in the lung following ozone exposure. The fact that ozone-induced lung injury and oxidative stress are reduced in CCR2^-/- mice suggests more prominent effects on proinflammatory macrophages.

SUBMITTER: Francis M

PROVIDER: S-EPMC5291213 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure.

Francis Mary M Groves Angela M AM Sun Richard R Cervelli Jessica A JA Choi Hyejeong H Laskin Jeffrey D JD Laskin Debra L DL

Toxicological sciences : an official journal of the Society of Toxicology 20161111 2

Ozone-induced lung injury is associated with an accumulation of activated macrophages in the lung. Chemokine receptor CCR2 mediates the migration of inflammatory monocytes/macrophages to sites of tissue injury. It is also required for monocyte egress from the bone marrow. In the present studies, we analyzed the role of CCR2 in inflammatory cell trafficking to the lung in response to ozone. Treatment of mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory CCR2<sup>+</sup> macro ...[more]

PMID: 27837169

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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.

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Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure.

Publications

Editor's Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure.

Similar Datasets

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