促炎细胞因子
T细胞
细胞生物学
生物
炎症
髓样
心脏纤维化
受体
纤维化
分子生物学
免疫学
内科学
医学
免疫系统
生物化学
作者
Abraham L Bayer,Sasha Smolgovsky,Njabulo Ngwenyama,Ana Hernández-Martínez,Kuljeet Kaur,Katherine B. Sulka,Junedh Amrute,Mark Aronovitz,Kory J. Lavine,Shruti Sharma,Pilar Alcaide
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2023-08-18
卷期号:133 (5): 412-429
被引量:3
标识
DOI:10.1161/circresaha.123.323030
摘要
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.We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88-/- mouse T cells at the transcript and protein level and performed several functional assays.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 wild type, 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.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.
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