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Meteorin-like regulates cardiac repair via macrophage modulation following myocardial infarction

ABSTRACT: After myocardial infarction (MI), the heart undergoes a reparative process that includes an initial acute inflammatory phase followed by a subsequent reparative phase. The transition between these phases is crucial for cardiac recovery, but the key factors remain unclear. Meteorin-like (Metrnl) promotes anti-inflammatory macrophage polarization in the myocardium, yet its role in the acute phase post-MI is unknown. We observed that macrophages infiltrating the ischemic myocardium produced elevated levels of Metrnl in both the heart and circulation 4 days post-MI. The absence of Metrnl in Metrnl⁻/⁻ mice altered myocardial healing and remodeling, with an increased presence of macrophages with a more pro-inflammatory phenotype. Conversely, cardiac Metrnl overexpression restored myocardial repair and promoted a shift toward a more anti-inflammatory macrophage phenotype. Mechanistically, Metrnl regulated macrophage-dependent production of Oncostatin M (Osm), a key cytokine in the early inflammatory phase post- MI that induces cardiomyocyte production of Reg3β. Reg3β, in turn, limits classical macrophage activation and polarization while modulating their trafficking, ultimately influencing the duration and intensity of the pro-inflammatory phase post-MI. Thus, Metrnl plays a crucial role in cardiac repair by modulating the acute phase following myocardial infarction through its regulation of macrophage populations.

ORGANISM(S): Mus musculus

PROVIDER: GSE335342 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:Inflammatory responses are crucial in the pathological cardiac remodeling and repair after myocardial infarction (MI). The lymphatic endothelial cells (LECs) significantly influence immune cell clearance and mitigate cardiac inflammation. Chemokines are known to tightly regulate immune cell mobilization within the infarcted heart, thereby significantly influencing cardiac inflammation and remodeling. However, the role of chemokines expressed by LECs in the regulation of cardiac inflammation post-MI remains unclear. Our study revealed that the expression of CC chemokine CCL2 in cardiac LECs was sharply un-regulated following MI. We thus hypothesized that lymphatic endothelial CCL2 might be involved in post-MI cardiac remodeling. To test this hypothesis, we generated LEC-conditional Ccl2 knock-out mice. In vivo experiments demonstrated that the LEC-Ccl2 deficiency deteriorated cardiac function and worsened adverse cardiac remodeling after MI. Further analysis showed that the loss of CCL2 in LECs impeded post-MI lymphangiogenesis and increased macrophage infiltration in post-MI myocardium and impaired macrophages clearance via afferent cardiac lymphatics. This led to exacerbated inflammatory responses and pathological cardiac remodeling after MI. Mechanistically, our study identified that LECs expressed and secreted CCL2, which played a dual role. LEC-CCL2 recruit macrophages from the infarcted myocardium into the lymphatic system and activated AKT/ETS1 signaling, enhancing VEGFC expression and promoting lymphangiogenesis in an autocrine manner. This study reveals that cardiac LEC-expressing CCL2 tightly control macrophage trafficking via lymphatic vessels in injured hearts and thus diminished post-MI inflammatory responses and lessened adverse cardiac remodeling. This study demonstrates that CCL2 expression in cardiac LECs tightly controls macrophage trafficking via lymphatic vessels in injured hearts, thereby diminishing post-MI inflammatory responses and lessening adverse cardiac remodeling. This study suggests that modulating CCL2 signaling in LECs could provide a promising therapeutic target for resolving excessive inflammation and ameliorating adverse cardiac remodeling after MI.

Project description:Myocardial infarction (MI) is a sterile inflammatory condition that results in the activation of T- cells targeting cardiac antigens. T-cells have been shown to contribute to reparative and maladaptive remodeling post-MI. However, the differentiation trajectories and in situ activity of heart-specific CD4+T cells and the effect of distinct T-cell phenotypes on MI repair remains poorly understood. Herein, we combined T-cell receptor transgenic models and tetramer staining targeting myocardial protein with single-cell transcriptomics (scRNAseq) and functional phenotyping to elucidate how the myosin-specific CD4+ T cells (TCR-M) differentiate in the murine infarcted myocardium and influence tissue repair. Furthermore, we transferred pro-inflammatory versus regulatory pre-differentiated heart-specific T-cells to dissect how they differentially regulate post-myocardial infarction (MI) inflammation. Flow cytometry and scRNAseq findings reveled that transferred TCR-M cells acquired an induced regulatory phenotype (iTreg) in the infarcted myocardium and blunt local inflammation. Myocardial TCR-M cells differentiated into two main lineages enriched with cell activation and pro-fibrotic transcripts (e.g. Tgfb1) or with suppressor immune checkpoints (e.g. Pdcd1), which we also found in human myocardial tissue. These cells produced high levels of latency-associated peptide (LAP) and inhibited interleukine-17 (IL-17) responses. Tetramer staining further identified endogenous myosin-specific T-cells that acquired a regulatory phenotype in the heart post-MI. Notably, TCR-M cells that were pre-differentiated in vitro towards a regulatory phenotype maintained a stable in vivo FOXP3 expression and anti-inflammatory activity whereas TH17 partially converted towards a regulatory phenotype in the injured myocardium, which was associated to blunted myocardial inflammation. Moreover, myocardial scar of Treg TCR-M transferred mice showed blunted inflammatory transcripts and enrichment for growth factors supporting fibroblasts and endothelial cells.

Project description:Background: Excess fibrotic remodeling leads to cardiac dysfunction in ischemic heart disease and is driven by MAP kinase-dependent transforming growth factor-ß1 (TGF-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is incompletely understood. Methods: Mice with permanent ligation of the proximal left anterior descending artery (LAD) were used to model ischemic heart disease and analyzed by single cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-factor 7 (F7)-integrin ß1-protease activated receptor (PAR) 2 signaling complex by utilizing genetic mouse models and pharmacological intervention. Results: Cleavage-insensitive PAR2R38E and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared to controls. Proximity ligation assays of monocytic cells in the infarcted myocardium demonstrated that colocalization of F7 with integrin ß1 was diminished in monocyte/macrophage F7-deficient mice. F7fl/fl CX3CR1Cre relative to littermate control mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells into the infarct zone. Single cell mRNA sequencing of CD45+ cells 3 and 7 days after MI uncovered a trajectory from ischemic myocardium-recruited monocytes to inflammatory TF+/F7+/TREM1+ macrophages. As early as 7 days after MI, macrophage F7-deletion led to an expansion of Olfml3+ macrophages with a reparative phenotype and, conversely, to a reduction of TF+/F7+/TREM1+ macrophages, which were also attenuated in activation-resistant PAR2R38E mice. To demonstrate the therapeutic potential of inhibiting the TF-F7-PAR2 signaling complex,, we injected a specific monoclonal anti-TF antibody that lacks anticoagulant activity, but interferes with macrophage migration in vitro. Short-term treatment from day 1-5 after non-reperfused MI improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI. Conclusions: Extravascular TF-F7-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.

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Meteorin-like regulates cardiac repair via macrophage modulation following myocardial infarction

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