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Single-cell RNA sequencing data indicate that CD40 promots macrophage efferocytosis following myocardial infarction.

ABSTRACT: CD40 expressed on the macrophage membrane is recognized as one of the characteristic biomarkers for their inflammatory phenotype. We demonstrated that macrophage CD40 functionally promotes post-myocardial infarction (MI) repair. To elucidate the role of CD40 in the post-MI repair process, we dissected infarct and border zones from the hearts of wild-type (WT) and CD40 knockout (KO) mice at 3 days post-MI. Mononuclear macrophages (CD45⁺CD11b⁺CD64⁺) were isolated via flow cytometry and subjected to single-cell RNA sequencing analysis. This study establishes that CD40 plays a critical role in macrophage efferocytosis. Furthermore, analysis of scRNA-seq data led to the identification of developmental precursor cells of repair-phenotype macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE322626 | GEO | 2026/05/01

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.

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Single-cell RNA sequencing data indicate that CD40 promots macrophage efferocytosis following myocardial infarction.

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