T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

Abstract

BACKGROUND: Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown. METHODS: We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled WT versus Myd88 −/− mouse T cells at the transcript and protein level and performed several functional assays. RESULTS: Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88 −/− T cells had increased proinflammatory signaling at the transcript and protein level compared with WT, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling. CONCLUSIONS: Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.

Cardiac fibrogenesis: an immuno-metabolic perspective

“…T-cell receptor engagement, antigenic stimuli, tissue microenvironment, and metabolic reprogramming shape the repertoire of T cells into that of T helper cells (Th1, Th2, Th9, Th17, and Th22), cytotoxic T lymphocytes (CTLs), regulatory T (T reg ) cells, and natural killer T (NKT) cells ( Zhang and Zhang, 2020 ) . Induction of T cells by cardiac DAMPs processed by antigen-presenting cells results in cardiotropism, transformation of cardiac fibroblasts, and maladaptive cardiac remodeling ( Bayer et al, 2023 ) ( Figure 2 ). An increasing body of literature indicates that distinct subpopulations of T lymphocytes play a substantial role in the direct stimulation of fibroblasts and progression of cardiac fibrosis ( Nevers et al, 2015 ; Li et al, 2017 ; Abdullah and Jin, 2018 ) .…”

Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities

“…116 The effects of MyD88 in the postinfarction inflammatory response may involve actions on several different cell types, including bone marrow-derived leukocytes, 117 resident cardiac macrophages, 118 cardiomyocytes, 115 and fibroblasts. 57 A recent study in a model of left ventricular pressure overload suggested important regulatory effects of MyD88 on T lymphocyte phenotype 119 ; however, the significance of these actions in MI has not been investigated. Endosomal TLR4 or TLR3 can also transduce proinflammatory signaling through MyD88-independent pathways, by recruiting another cytoplasmic adaptor protein called TRIF (TIR domain-containing adaptor inducing IFN [interferon]-β).…”