Emerging Role of Macrophage-Fibroblast Interactions in Cardiac Homeostasis and Remodeling

Abstract

As major noncardiomyocyte components in cardiac tissues, macrophages and fibroblasts play crucial roles in maintaining cardiac homeostasis, orchestrating reparative responses after cardiac injuries, facilitating adaptive cardiac remodeling, and contributing to adverse cardiac remodeling, owing to their inherent heterogeneity and plasticity. Recent advances in research methods have yielded novel insights into the intricate interactions between macrophages and fibroblasts in the cardiac context. This review aims to comprehensively examine the molecular mechanisms governing macrophage-fibroblast interactions in cardiac homeostasis and remodeling, emphasize recent advancements in the field, and offer an evaluation from a translational standpoint.

Keywords: cardiac homeostasis; cardiac remodeling; fibroblast; intercellular interaction; macrophage.

Graphical abstract

Figure 1

The Phenotypic and Functional Characteristics of Cardiac Macrophages and Fibroblasts (A) Current mainly investigated macrophage subtypes in cardiac homeostasis and remodeling. RCM (resident cardiac macrophage) refers to macrophage subsets that exist in the heart under steady state and are derived primarily from embryonic progenitors. During cardiac remodeling, peripheral monocyte-derived macrophage (moMφs) dominate the injured heart. (B) Fibroblast dynamics in cardiac homeostasis and remodeling. The steady-state heart is populated by resident mature fibroblasts. On cardiac injury, mature cardiac fibroblasts transform into activated fibroblasts and exhibit elevated proliferation and collagen production. A proportion of activated fibroblasts undergo transdifferentiation into myofibroblasts, a more profibrotic and contractile phenotype characterized by significantly increased synthesis of contractile proteins. CCR2 = C-C chemokine receptor 2; ECM = extracellular matrix; FAP = fibroblast activation protein; IGF = insulin-like growth factor; IL = interleukin; Ly6C = lymphocyte antigen 6C; LYVE1 = lymphatic vessel endothelial hyaluronan receptor 1; MHC-II = major compatibility complex II; OPN = osteopontin; PDGFR = platelet-derived growth factor receptor; SMA = smooth muscle actin; TLF = expression of Timd4, Lyve1, and Folr2; TREM2 = triggering receptor expressed on myeloid cells 2.

Figure 2

Cardiac Macrophage and Fibroblast Dynamics in the Infarcted and the Pressure-Overloaded Myocardium (A) Acute ischemic injury results in a significant reduction of RCMs and recruitment of proinflammatory moMφs in the infarcted myocardium, and mature resident fibroblasts are activated into a proliferative and more collagen-producing phenotype. During the reparative phase, moMφs exhibit a proreparative and antiinflammatory phenotype, that supports myofibroblast differentiation and scar formation, and RCMs show slow recovery through local proliferation. During the scar maturation phase, the majority of cardiac macrophages gradually diminish. (B) In the pressure-overloaded myocardium induced via transverse aortic constriction surgery, RCMs proliferate significantly during adaptive remodeling, while they decrease during adverse remodeling and heart failure progression. Recruited moMφs continue to infiltrate and induce proinflammatory and profibrotic cascades. MHC-II = major compatibility complex II; moMφ = monocyte-derived macrophage; RCM = resident cardiac macrophage; TLF = expression of Timd4, Lyve1, and Folr2.

Central Illustration

The Integrated Landscape of Macrophage-Fibroblast Interactions in Cardiac Homeostasis and Remodeling (A) In the steady-state heart, intramyocardial spaces are predominantly occupied by embryonic RCMs and mature fibroblasts, both of which play organ-specific roles in maintaining cardiac homeostasis. (B) Acute ischemic injury results in extensive cell death, including cardiomyocytes and RCMs. The subsequent release of damage-associated molecular patterns leads to the recruitment of monocytes and differentiation into moMφs, exhibiting a proinflammatory phenotype and participating in efferocytosis to clear cellular debris. Simultaneously, environmental growth factors activate fibroblasts, promoting their transition into a proliferative and more collagen-producing phenotype. Once cellular debris is removed, environmental cues drive moMφ polarization, adopting a proreparative and antiinflammatory phenotype that supports cardiac repair and scar formation. Profibrotic signaling further induces transdifferentiation of activated fibroblasts into myofibroblasts, contributing to the maturation of cardiac scars. (C) During adaptive cardiac remodeling, embryonic RCMs proliferate and produce insulin-like growth factor-1 to facilitate adaptive growth of cardiomyocytes. Simultaneously, mechanical stress activates fibroblasts, leading to ECM remodeling and the infiltration of moMφs. (D) In adverse cardiac remodeling, embryonic RCMs experience a significant reduction and are replaced by moMφs. Sustained profibrotic signals activate cardiac fibroblasts, affecting the uninjured myocardium, resulting in reactive fibrosis and the development of chronic heart failure. (E) Through intercellular mediators, cardiac macrophages and fibroblasts interact to mutually regulate their abundance, location, phenotype and function, participating in cardiac homeostasis and remodeling. CCL2 = C-C chemokine ligand 2; CCL5 = C-C chemokine ligand 5; CCR2 = C-C chemokine receptor 2; CSF = colony-stimulating factor; CSF-1R = colony-stimulating factor-1 receptor; CXCL12 = C-X-C motif chemokine 12; ECM = extracellular matrix; Gal = galectin; IL = interleukin; miR = microRNA; MMP = matrix metalloproteinase; moMφ = monocyte-derived macrophage; OPN = osteopontin; PDGF = platelet-derived growth factor; PDGFR = platelet-derived growth factor receptor; RCM = resident cardiac macrophage; TGF = transforming growth factor; TNF = tumor necrosis factor.