Dataset Information

Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling.

ABSTRACT:

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

This study utilized Card9^-/- mice and reconstituted C57BL/6 mice with either Card9^-/- or Otud1^-/- 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 and remodelling.

Conclusions

These results suggested that the OTUD1-CARD9 axis is a new pro-inflammatory signal in ISO-challenged macrophages and targeting this axis has a protective effect against ISO-induced HF.

Key points

Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration. Either whole-body CARD9 knockout or myeloid-specific CARD9 deficiency protected mice from ISO-induced inflammatory heart remodeling. ISO promoted the assembly of CBM complex and then activated NF-κB signaling in macrophages through OTUD1-mediated deubiquitinating modification. OTUD1 deletion in myeloid cells protected hearts from ISO-induced injuries in mice.

SUBMITTER: Qian J

PROVIDER: S-EPMC11310286 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling.

Qian Jinfu J Wang Qinyan Q Xu Jiachen J Liang Shiqi S Zheng Qingsong Q Guo Xiaocheng X Luo Wu W Huang Weijian W Long Xiaohong X Min Julian J Wang Yi Y Wu Gaojun G Liang Guang G

Clinical and translational medicine 20240801 8

<h4>Background</h4>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.<h4>Methods</h4>This study utilized Card9<sup>-/-</sup> mice and reconstituted C57BL/6 mice with either Card9<sup>-/-</sup> or Otud1<sup>-/-</sup> marrow-derived c ...[more]

PMID: 39118286

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Dataset Information

Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling.

Background

Methods

Results

Conclusions

Key points

Publications

Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling.

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