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RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1–TLR4–NF‐κB pathway in macrophages
Author(s) -
Wei Song,
Zhou Haoming,
Wang Qi,
Zhou Shun,
Li Changyong,
Liu Rui,
Qiu Jiannan,
Shi Chengyu,
Lu Ling
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900752r
Subject(s) - fibrosis , rock1 , tlr4 , inflammation , liver injury , hepatic fibrosis , proinflammatory cytokine , macrophage , cancer research , immunology , medicine , biology , chemistry , pathology , endocrinology , protein kinase a , kinase , microbiology and biotechnology , biochemistry , in vitro
Liver fibrosis is an important pathologic process in injured liver tissues. A protein kinase, receptor‐interacting protein (RIP)3, plays a crucial role in mediating different diseases. However, the role of RIP3 in macrophages in liver fibrosis has not yet been studied. In our study, we found that RIP3 expression was up‐regulated in liver tissues and macrophages of humans and mice with liver fibrosis. Absence of RIP3 in macrophages could alleviate inflammation and macrophage or neutrophil accumulation in mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. Importantly, RIP3 deficiency in macrophages could decrease CCl 4 ‐induced and BDL‐induced liver fibrosis in mice. Moreover, RIP3 deficiency could inhibit the TLR4–NF‐κB pathway through suppressing Rho‐associated coiled‐coil containing protein kinase (ROCK)l in macrophages. To explore the connection of ROCK1 and RIP3 in macrophages of mice with liver fibrosis in vivo , ROCK1‐overexpressed macrophages were infused to RIP3‐deficient mice, which resulted in increased inflammation and liver fibrosis. In conclusion, our findings suggest that RIP3 plays a crucial proinflammatory role in liver fibrosis by regulating the ROCK1–TLR4–NF‐κB signaling pathway in macrophages and therefore may be a potential therapeutic target for immune‐mediated liver fibrosis.—Wei, S., Zhou, H., Wang, Q., Zhou, S., Li, C, Liu, R., Qiu, J., Shi, C, Lu, L. RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1‐TLR4‐NF‐κB pathway in macrophages. FASEB J. 33, 11180–11193 (2019). www.fasebj.org