Resident Cardiac Macrophages Mediate Adaptive Myocardial Remodeling

Abstract

SummaryCardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2−) macrophages. Herein, we identify an essential role for CCR2− macrophages in the chronically failing heart. Depletion of CCR2− macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2− macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4) dependent pathway that controlled growth factor expression. These findings establish a role for tissue resident macrophages in adaptive cardiac remodeling and introduce a new mechanism of cardiac macrophage activation.

Nrf2 attenuates the innate immune response after experimental myocardial infarction

“…These macrophages later shift to a reparative M2 phenotype, secrete anti-inflammatory cytokines, and instigate myocardial repair (14)(15)(16). Single cell (sc) RNA-seq experiments have implicated cardiac resident macrophages (RMs) in mediating the inflammatory response to cardiac injury (17)(18)(19). C-C chemokine receptor 2expressing (CCR2 + ) RMs (derived from recruited monocytes) and CCR2 -RMs (maintained independent of monocyte recruitment) promote and inhibit, respectively, monocyte recruitment after MI (20).…”

The role of endogenous Smad7 in regulating macrophage phenotype following myocardial infarction

“…18,19 In the remodeling non-infarcted myocardium, mechanical stress may activate macrophages and can contribute to adverse fibrotic remodeling and dysfunction. 10,20 The members of the TGF-β superfamily potently modulate myeloid cell phenotype and function. 21,22 In the healing infarct, all three TGF-β isoforms are induced and activated, and have been suggested to regulate inflammation, repair, remodeling, and fibrosis.…”

Developmental endothelial locus-1 in cardiovascular and metabolic diseases: a promising biomarker and therapeutic target

“…Regulation of immune function and inflammatory response is an important strategy for the treatment of CVMDs [20][21][22][23][24]. Increasing evidences show that tissue-resident immune cells are involved in regulating the pathophysiological processes of CVMDs [25][26][27][28]. Local tissues, such as vascular endothelium and adipose tissue, also have an important impact on the occurrence and development of CVMDs [29][30][31][32].…”