Leukocyte-Dependent Regulation of Cardiac Fibrosis

Abstract

Cardiac fibrosis begins as an intrinsic response to injury or ageing that functions to preserve the tissue from further damage. Fibrosis results from activated cardiac myofibroblasts, which secrete extracellular matrix (ECM) proteins in an effort to replace damaged tissue; however, excessive ECM deposition leads to pathological fibrotic remodeling. At this extent, fibrosis gravely disturbs myocardial compliance, and ultimately leads to adverse outcomes like heart failure with heightened mortality. As such, understanding the complexity behind fibrotic remodeling has been a focal point of cardiac research in recent years. Resident cardiac fibroblasts and activated myofibroblasts have been proven integral to the fibrotic response; however, several findings point to additional cell types that may contribute to the development of pathological fibrosis. For one, leukocytes expand in number after injury and exhibit high plasticity, thus their distinct role(s) in cardiac fibrosis is an ongoing and controversial field of study. This review summarizes current findings, focusing on both direct and indirect leukocyte-mediated mechanisms of fibrosis, which may provide novel targeted strategies against fibrotic remodeling.

Keywords: cardiac fibrosis; dendritic cells; eosinophils; inflammation; lymphocytes; mast cells; monocyte macrophage; neutrophil.

FIGURE 1

This graphical abstract summarizes the role of leukocytes in cardiac fibrosis. Following injury, damaged cardiac tissue (inclusive of all resident cell types) can release inflammatory mediators like DAMPs, which trigger an influx of leukocytes to the site of injury. Activated leukocytes then function through numerous mechanisms to regulate pathological cardiac fibrosis. Briefly, granulocytes (mast cells, eosinophils, neutrophils) have been shown to influence fibrosis in part, through their ability to secrete fibrotic mediators, regulate expression of MMPs/TIMPs and form inflammatory extracellular traps, respectively. Additionally, recent studies have identified varying subsets of macrophages and dendritic cells which differentially regulate fibrosis outcomes; cells of monocytic origin have also been examined for their direct contribution in myofibroblast differentiation. Lastly, numerous findings also implicate lymphocytes in cardiac fibrosis, these adaptive immune cells have been shown to influence remodeling outcomes through many mechanisms. BL, b lymphocyte; TL, t lymphocyte; preDC, precursor dendritic cell; NT, neutrophil; MC, mast cell; Mo, monocyte; Eo, eosinophil; Mϕ, macrophage; DC, dendritic cell; CM, cardiomyocyte; FB, fibroblast; MyoFB, myofibroblast; DAMP, damage associated molecular pattern; MPO, myeloperoxidase; NGAL, neutrophil gelatinase-associated lipocalin; N1, inflammatory NT; N2, antiinflammatory NT; NETosis, NT extracellular trap formation; GAL3, galectin-3; TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor alpha; FGF, fibroblast growth factor; PDGF, platelet derived growth factor; CCR2, C-C chemokine receptor 2; CX3CR1, CX3C chemokine receptor 1; IL-1β, interleukin 1 beta; IL-10, interleukin 10; Cyt, cytokines; Chk, chemokines; MMP2, matrix metallopeptidase 2; TIMP 2, tissue inhibitor of metalloproteinases 2; cDC, conventional DC; CD, cluster of differentiation; IL-6, interleukin 6; IFNγ, interferon gamma; Th1, t helper type 1; Treg, regulatory t cells. Graphics were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Uniported License; https://smart.servier.com.