Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis

Abstract

Rationale: The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages (mψs) in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac-resident immune cells influence the early phase of hypertrophy development has not been established. Objective: To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload-induced by transverse aortic constriction (TAC). Methods and Results: We performed cytometry-by-time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac mψs 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and mψs, categorized as either resident or recruited mψs, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac-resident mψs early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited mψs by monocytes before performing TAC. This preferential depletion of resident mψs resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Mψ-depletion in CCR2 knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived mψs. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells. Conclusions: Cardiac resident mψs are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.

Cardiac Macrophages and Their Effects on Arrhythmogenesis

“…Studies on cardiac remodeling after tissue injury (e.g. myocardial infarction) revealed that macrophages play a pivotal role in cardiac remodeling as they may have both profibrotic and antifibrotic functions ( Wynn and Barron, 2010 ; Liao et al, 2018 ; Revelo et al, 2021 ; Dobaczewski et al, 2011 ). CD68 + or CD11c + macrophages infiltrate the epicardial adipose tissue of AF patients and are associated with atrial fibrotic remodeling leading to a proarrhythmic substrate for AF ( Abe et al, 2018 ).…”

“…Pro-inflammatory macrophages release cytokines and chemokines and have been demonstrated to be involved in electrical ( Monnerat et al, 2016 ; Sun et al, 2016 ; Fei et al, 2019 ; Liu et al, 2019 ; Zhang et al, 2020 ) as well as autonomic remodeling of the heart ( Yin et al, 2016 ; Hu et al, 2019 ; Lyu et al, 2020 ; Zhang et al, 2021 ). Noncanonical reparative (or alternatively-activated) macrophages release anti-inflammatory cytokines, participate in post-inflammatory tissue repair, and contribute to cardiac structural remodeling by promoting cardiac fibrosis ( Wynn and Barron, 2010 ; Dobaczewski et al, 2011 ; Mills, 2012 ; Liao et al, 2018 ; Miyosawa et al, 2020 ; Watson et al, 2020 ; Hiram et al, 2021 ; Revelo et al, 2021 ). Furthermore, it has been shown that cardiac resident macrophages are functionally connected to cardiomyocytes by gap junctions ( Simon-Chica et al, 2022 ), thereby facilitating the physiologic electrical conduction in the atrioventricular (AV) node ( Hulsmans et al, 2017 ) or preserving electrical conduction in the context of disease ( Sugita et al, 2021 ).…”

Early Protective Role of Inflammation in Cardiac Remodeling and Heart Failure: Focus on TNFα and Resident Macrophages

“…In contrast, a potential protective role of self-renewing resident-Mφ (CCR 2 − ) has emerged from recent studies [ 137 , 156 , 169 , 172 , 173 ] ( Figure 4 ).…”

“…In addition, VEGF secreted by resident Mφ is a well-known key mediator of angiogenesis, e.g., in response to TAC [ 172 , 173 ] ( Figure 4 ).…”

“…In patients with cardiomyopathy, CCR 2 − Mφ seem to locate near the coronary vasculature, similarly to what has been reported for mice, whereas CCR 2 + Mφ occupy fibrotic areas [ 161 ]. Cardiac-resident Mφ were reported to limit cardiac fibrosis in a pressure overload model [ 172 ] ( Figure 4 ). Interestingly, Deniset et al describe the pericardial cavity as an important source of resident Gata6 + Mφ that migrate into the heart, limit fibrosis of healthy myocardium, and improve functional cardiac recovery after ischemic injury, preventing detrimental repair caused by excessive fibrosis [ 221 ].…”