Macrophage OTUD1‐CARD9 axis drives isoproterenol‐induced inflammatory heart remodelling

作者：Jinfu Qian, Qinyan Wang, Jiachen Xu, Shiqi Liang, Qingsong Zheng, Xiaocheng Guo, Wu Luo, Weijian Huang, Xiaohong Long, Julian Min, Yi Wang, Gaojun Wu, Guang Liang · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.1790 · 被引用次数：22 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiac Ischemia and Reperfusion、Congenital heart defects research

BACKGROUND: Chronic inflammation contributes to the progression of isoproterenol (ISO)-induced heart failure (HF). Caspase-associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO-driven cardiac remodelling is little explored. METHODS: marrow-derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK-293T cells. RESULTS: Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole-body CARD9 knockout or myeloid-specific CARD9 deletion inhibited ISO-driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO-induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33-linked ubiquitin from CARD9 to promote the assembly of the CARD9-BCL10-MALT1 (CBM) complex, without affecting CARD9 stability. The ISO-activated CBM complex results in NF-κB activation and macrophage-based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid-specific OTUD1 deletion also attenuated ISO-induced murine cardiac inflammation a...