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Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

ABSTRACT: OBJECTIVE:Extracellular vesicles secreted by cardiosphere-derived cells (CDCev) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (MCDCev). These changes underlie cardioprotection by CDCev and by the parent CDCs, notably attenuating the no-reflow phenomenon following myocardial infarction, but the mechanisms are unclear. Here, we tested the hypothesis that MCDCev are especially effective at scavenging debris from dying cells (ie, efferocytosis) to attenuate irreversible damage post-myocardial infarction. Approach and Results: In vitro efferocytosis assays with bone marrow-derived macrophages, and in vivo transgenic rodent models of myocardial infarction, demonstrate enhanced apoptotic cell clearance with MCDCev. CDCev exposure induces sustained MerTK expression in MCDCev through extracellular vesicle transfer of microRNA-26a (via suppression of Adam17); the cardioprotective response is lost in animals deficient in MerTK. Single-cell RNA-sequencing revealed phagocytic pathway activation in MCDCev, with increased expression of complement factor C1qa, a phagocytosis facilitator. CONCLUSIONS:Together, these data demonstrate that extracellular vesicle modulation of MerTK and C1qa expression leads to enhanced macrophage efferocytosis and cardioprotection.

SUBMITTER: de Couto G

PROVIDER: S-EPMC6760997 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

de Couto Geoffrey G Jaghatspanyan Ervin E DeBerge Matthew M Liu Weixin W Luther Kristin K Wang Yizhou Y Tang Jie J Thorp Edward B EB Marbán Eduardo E

Arteriosclerosis, thrombosis, and vascular biology 20190822 10

<h4>Objective</h4>Extracellular vesicles secreted by cardiosphere-derived cells (CDC<sub>ev</sub>) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (M<sub>CDCev</sub>). These changes underlie cardioprotection by CDC<sub>ev</sub> and by the parent CDCs, notably attenuating the no-reflow phenomenon following myocardial infarction, but the mechanisms are unclear. Here, we tested the hypothesis that M<sub>CDCev</sub> are especially effective at scavenging debris ...[more]

PMID: 31434491

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Project description:Background & aimsThe mechanisms by which hepatocyte exposure to alcohol activates inflammatory cells such as macrophages in alcoholic liver disease (ALD) are unclear. The role of released nano-sized membrane vesicles, termed extracellular vesicles (EV), in cell-to-cell communication has become increasingly recognized. We tested the hypothesis that hepatocytes exposed to alcohol may increase EV release to elicit macrophage activation.MethodsPrimary hepatocytes or HepG2 hepatocyte cell lines overexpressing ethanol-metabolizing enzymes alcohol dehydrogenase (HepG2(ADH)) or cytochrome P450 2E1 (HepG2(Cyp2E1)) were treated with ethanol and EV release was quantified with nanoparticle tracking analysis. EV mediated macrophage activation was monitored by analysing inflammatory cytokines and macrophage associated mRNA expression, immunohistochemistry, biochemical serum alanine aminotransferase and triglycerides analysis in our in vitro macrophage activation and in vivo murine ethanol feeding studies.ResultsEthanol significantly increased EV release by 3.3-fold from HepG2(Cyp2E1) cells and was associated with activation of caspase-3. Blockade of caspase activation with pharmacological or genetic approaches abrogated alcohol-induced EV release. EV stimulated macrophage activation and inflammatory cytokine induction. An unbiased microarray-based approach and antibody neutralization experiments demonstrated a critical role of CD40 ligand (CD40L) in EV mediated macrophage activation. In vivo, wild-type mice receiving a pan-caspase, Rho kinase inhibitor or with genetic deletion of CD40 (CD40(-/-)) or the caspase-activating TRAIL receptor (TR(-/-)), were protected from alcohol-induced injury and associated macrophage infiltration. Moreover, serum from patients with alcoholic hepatitis showed increased levels of CD40L enriched EV.ConclusionIn conclusion, hepatocytes release CD40L containing EV in a caspase-dependent manner in response to alcohol exposure which promotes macrophage activation, contributing to inflammation in ALD.

Dataset Information

Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

Publications

Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

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