The Roles of Cardiac Fibroblasts and Endothelial Cells in Myocarditis

Abstract

In myocarditis caused by various etiologies, activated immune cells and the immune regulatory factors released by them play important roles. But in this complex microenvironment, non-immune cells and non-cardiomyocytes in the heart, such as cardiomyocytes (CMs), cardiac fibroblasts (CFs) and endothelial cells (ECs), play the role of "sentinel", amplify inflammation, and interact with the cardiomyocytes. The complex interactions between them are rarely paid attention to. This review will re-examine the functions of CFs and ECs in the pathological conditions of myocarditis and their direct and indirect interactions with CMs, in order to have a more comprehensive understanding of the pathogenesis of myocarditis and better guide the drug development and clinical treatment of myocarditis.

Keywords: cardiac fibroblasts; cross-talk; endothelial cells; extracellular vesicles; myocarditis.

Figure 1

Fibroblast and endothelial cell activation. Fibroblasts are activated in viral infection or in the environment containing cytokines. Then they produce pro-inflammatory factors and chemokines such as TNF-α, IL-6, MCP-1, IFN-β, CCL11, CCL12. They can also produce MMP family proteins to regulate cardiac interstitial fibrosis. Under the stimulation of these microenvironments, endothelial cells produce adhesion molecules to regulate the adhesion and infiltration of inflammatory cells. The participation of fibroblasts and endothelial cells promotes more severe cardiac inflammatory infiltration and more severe fibrosis.

Figure 2

Fibroblasts, endothelial cells and cardiomyocytes interaction diagram. Fibroblasts, endothelial cells can interact with cardiomyocytes through mechanical coupling and electrical coupling. They also act through paracrine effects and/or cell-secreted vesicles or exosomes. Cardiomyocytes secrete pro-inflammatory factors such as TNF-α, IL-1β, and IL-6 through paracrine effects to act on fibroblasts, and they can also deliver intracellular miRNAs through exosomes, such as miR92a, miR195, and miR378. These mediators can affect fibroblast proliferation, migration, differentiation and matrix production. Fibroblasts can also secrete factors such as TGF-β through paracrine action or deliver miRNAs into cardiomyocytes through exosomes, which affect cardiomyocyte contraction and cardiac hypertrophy. Similarly, endothelial cells can secrete effector molecules such as IL-8 through paracrine effects, and can also carry ROS through exosomes, thereby affecting various functions of cardiomyocytes. In contrast, cardiomyocytes can affect endothelial cell migration, proliferation, and angiogenesis by secreting exosomes carrying molecules such as miR-21.