Dataset Information

CCR2⁺ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.

ABSTRACT: Although chronic inflammation is a central feature of heart failure (HF), the immune cell profiles differ with different underlying causes. This suggests that for immunomodulatory therapy in HF to be successful, it needs to be tailored to the specific etiology. Here, the authors demonstrate that monocyte-derived C-C chemokine receptor 2 (CCR2)⁺ macrophages infiltrate the heart early during pressure overload in mice, and that blocking this response either pharmacologically or with antibody-mediated CCR2⁺ monocyte depletion alleviates late pathological left ventricular remodeling and dysfunction, T-cell expansion, and cardiac fibrosis. Hence, suppression of CCR2⁺ monocytes/macrophages may be an important immunomodulatory therapeutic target to ameliorate pressure-overload HF.

SUBMITTER: Patel B

PROVIDER: S-EPMC6059350 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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CCR2<sup>+</sup> Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.

Patel Bindiya B Bansal Shyam S SS Ismahil Mohamed Ameen MA Hamid Tariq T Rokosh Gregg G Mack Matthias M Prabhu Sumanth D SD

JACC. Basic to translational science 20180314 2

Although chronic inflammation is a central feature of heart failure (HF), the immune cell profiles differ with different underlying causes. This suggests that for immunomodulatory therapy in HF to be successful, it needs to be tailored to the specific etiology. Here, the authors demonstrate that monocyte-derived C-C chemokine receptor 2 (CCR2)<sup>+</sup> macrophages infiltrate the heart early during pressure overload in mice, and that blocking this response either pharmacologically or with anti ...[more]

PMID: 30062209

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Project description:Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (n = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, p < 0.05), increased contractility (QRS and QTc, p < 0.05), and less inflammation (e.g., interleukins 6 and 1β, p < 0.05) after TAC compared to WT animals (n = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, p < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, p = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.

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.

Dataset Information

CCR2⁺ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.

Publications

CCR2<sup>+</sup> Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.

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CCR2+ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.

Publications

CCR2<sup>+</sup> Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CCR2⁺ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload.