Cardiac fibrogenesis: an immuno-metabolic perspective

Abstract

Cardiac fibrosis is a major and complex pathophysiological process that ultimately culminates in cardiac dysfunction and heart failure. This phenomenon includes not only the replacement of the damaged tissue by a fibrotic scar produced by activated fibroblasts/myofibroblasts but also a spatiotemporal alteration of the structural, biochemical, and biomechanical parameters in the ventricular wall, eliciting a reactive remodeling process. Though mechanical stress, post-infarct homeostatic imbalances, and neurohormonal activation are classically attributed to cardiac fibrosis, emerging evidence that supports the roles of immune system modulation, inflammation, and metabolic dysregulation in the initiation and progression of cardiac fibrogenesis has been reported. Adaptive changes, immune cell phenoconversions, and metabolic shifts in the cardiac nonmyocyte population provide initial protection, but persistent altered metabolic demand eventually contributes to adverse remodeling of the heart. Altered energy metabolism, mitochondrial dysfunction, various immune cells, immune mediators, and cross-talks between the immune cells and cardiomyocytes play crucial roles in orchestrating the transdifferentiation of fibroblasts and ensuing fibrotic remodeling of the heart. Manipulation of the metabolic plasticity, fibroblast-myofibroblast transition, and modulation of the immune response may hold promise for favorably modulating the fibrotic response following different cardiovascular pathological processes. Although the immunologic and metabolic perspectives of fibrosis in the heart are being reported in the literature, they lack a comprehensive sketch bridging these two arenas and illustrating the synchrony between them. This review aims to provide a comprehensive overview of the intricate relationship between different cardiac immune cells and metabolic pathways as well as summarizes the current understanding of the involvement of immune-metabolic pathways in cardiac fibrosis and attempts to identify some of the previously unaddressed questions that require further investigation. Moreover, the potential therapeutic strategies and emerging pharmacological interventions, including immune and metabolic modulators, that show promise in preventing or attenuating cardiac fibrosis and restoring cardiac function will be discussed.

Keywords: cardiac fibrosis; cardiometabolism; immune cells; immunometabolism; inflammation; metabolic reprogramming.

FIGURE 1

Overview of cellular steps leading to cardiac fibrosis. Following injury, cardiac fibroblasts are activated and transdifferentiated into myofibroblasts to replace dying cardiomyocytes. Dying myocytes release damage-associated molecular patterns (DAMPs) which activate immune cells and trigger downstream signaling cascades of pro-inflammatory cytokines and chemokines. A plethora of cytokines and chemokines in addition to myofibroblasts undergo metabolic alterations that drive the development and progression of myocardial fibrosis and heart failure. Figure created using BioRender.

FIGURE 2

Immune crosstalk between inflammatory cells and cardiac cells during the transformation of the cardiac microenvironment toward fibrosis. The injured myocardium alters the cardiac microenvironment and releases different growth factors and inflammatory mediators, i.e., IL-6, IL-1β, GM-CSF, TNF-α, PDGF, and DAMPs, from injured cardiomyocytes, cardiac fibroblasts, endothelial cells, and pericytes (Gwechenberger et al., 1999; MeléNdez et al., 2010a; Anzai et al., 2017). Upon activation, cardiac fibroblasts further promote the cascades and release MMPs, TIMPs, MCP-1, and TNF-α, which play a role in ECM remodeling and fibrogenesis (Yoshimura et al., 2014; Pluijmert et al., 2021). During these events, the recruited and activated immune cells release another wave of cytokines and chemokines which further promote cardiac remodeling. Recruited monocytes and macrophages trigger inflammatory responses by releasing DAMPs, detect extracellular DNA from dying cells, and release type I interferons (King et al., 2017). Resident macrophages, IL-10 signaling, and MERTK modulate inflammatory cells, promote reparative events, inhibit hyperactivation of fibroblasts, and mitigate fibrosis (DeBerge et al., 2017; Jung et al., 2017; Revelo et al., 2021). Simultaneously, neutrophils, lymphocytes, and mast cells crosstalk with macrophages and fibroblasts to stage the background of ECM turnover and deposition of collagen by releasing inflammatory cytokines. Dendritic cells and NK cells contribute to improving fibrosis by modulating adverse inflammatory events (Ong et al., 2015; Choo et al., 2017). When these profibrotic interplay and crosstalk between different resident and non-resident immune and non-immune cells in the stressed heart outweigh the reparatory mechanisms, the consequential events ultimately lead to cardiac fibrosis. Abbreviations: MERTK, proto-oncogene tyrosine-protein kinase MER; NGAL, neutrophil gelatinase-associated lipocalin; IFNγ, interferon gamma; TNF-α, tumor necrosis factor-alpha; IL1β, interleukin-1 beta; IL6, interleukin 6; IL15, interleukin 15; IL12, interleukin 12; IL8, interleukin 8; IL17, interleukin 17; IL9, interleukin 9; IL4, interleukin 4; IL13, interleukin 13; MMP, matrix metalloproteinase; TIMP, tissue inhibitors of metalloproteinases; SMAD, suppressor of mothers against decapentaplegic; IRF3, interferon regulatory factor 3; MPO, myeloperoxidase; NET, neutrophil extracellular traps; GM-CSF, granulocyte–macrophage colony-stimulating factor; DAMP, damage-associated molecular pattern; Snail, zinc finger protein SNAIL1; SLC, solute carrier; MCP-1, monocyte chemoattractant protein-1; VEGF, vascular endothelial growth factor; EGF, epidermal growth factor; EAR1, eosinophil-associated ribonuclease 1. Figure created using BioRender.

FIGURE 3

Interplay of inflammatory cells with fibroblasts and cardiomyocytes and their metabolic reprogramming in cardiac fibrogenesis. DAMPs from the damaged cardiomyocytes and mitochondrial ROS activate macrophages and fibroblasts and bring about metabolic changes to meet the altered metabolic demand. Increased glycolysis and amino acid utilization and decreased oxidative phosphorylation in macrophages, neutrophils, and lymphocytes promote the release of different growth and inflammatory factors, i.e., IL-1β, IL-12, PDGF, and ROS, which subsequently activate fibroblasts (Wang et al., 2008; Yoshikawa et al., 2022). Metabolic shifts promote the production of lactate, succinate, HIF1-α, and TCA cycle intermediates and stimulate myofibroblast differentiation. Myofibroblasts shift from fatty acid oxidation to glutaminolysis and promote αKG and collagen biosynthesis and fibrotic deposition in the heart (Gibb et al., 2022a; Fan et al., 2023). Abbreviations: DAMP, damage-associated molecular pattern; FA synthesis, fatty acid synthesis; HIF1, hypoxia-inducible factor 1; IL-1β, interleukin-1 beta; IL-12, interleukin-4; MIP1β, macrophage inflammatory protein-1 beta; mtROS, mitochondrial reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; OXPHOS, oxidative phosphorylation; PDGF, platelet-derived growth factor; PPP, pentose phosphate pathway; TCA cycle, tricarboxylic acid cycle; TGF-β, transforming growth factor-beta. Figure created using BioRender.

FIGURE 4

Interdependence of metabolism and ECM remodeling. Fibroblasts and macrophages work in concert to regulate the ECM. They are the primary cell types that mediate collagen internalization and degradation. For instance, fibroblasts and macrophages activate glycolysis, via TGF-β signaling, and promote fibrosis. Glycolysis, in turn, can increase TGF-β, further activating fibroblasts and macrophages. Fibroblasts and macrophages also activate beta-oxidation via PPAR signaling to promote degradation of the ECM. PPARγ can control macrophage polarization to either pro-inflammatory M1 or to anti-inflammatory M2 macrophages. Figure created using BioRender.

FIGURE 5

Targeting metabolism and immunity in cardiac fibrosis. Cellular map showing the sites of possible potential interventions in immune and metabolic pathways to improve the outcome of cardiac fibrosis. Figure created using BioRender.