MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs

• Published in: International journal of molecular sciences 2021-11, Vol.22 (22), p.12413
• Main Authors: Ge, Shuang, Yang, Wei, Chen, Haiqiang, Yuan, Qi, Liu, Shi, Zhao, Yongxiang, Zhang, Jinhua
• Format: Article
• Language: English
• Subjects: Adaptor proteins; Animals; Bone marrow; Carbon tetrachloride; Carbon Tetrachloride - adverse effects; CCL4 protein; Cell activation; Cell Line; Chemokine CXCL2 - metabolism; Chemokine CXCL2 - pharmacology; Chemokines; Coculture Techniques; Collagen; CXCR2 protein; Cytokines; Disease Models, Animal; Female; Fibrosis; Flow cytometry; Gene Deletion; Gene expression; Hepatic Stellate Cells - metabolism; Hepatitis; Hepatocytes; HSC; Humans; Inflammasomes; Inflammasomes - metabolism; Inflammation; Liver; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver diseases; liver fibrosis; macrophage; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MyD88; MyD88 protein; Myeloid cells; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Pyrin protein; Rodents; Roles; Signal Transduction - drug effects; Signal Transduction - genetics; Stellate cells; Toll-like receptors; Transgenic animals
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222212413

Chronic liver disease mediated by the activation of hepatic stellate cells (HSCs) leads to liver fibrosis. The signal adaptor MyD88 of Toll-like receptor (TLR) signaling is involved during the progression of liver fibrosis. However, the specific role of MyD88 in myeloid cells in liver fibrosis has not been thoroughly investigated. In this study, we used a carbon tetrachloride (CCl )-induced mouse fibrosis model in which MyD88 was selectively depleted in myeloid cells. MyD88 deficiency in myeloid cells attenuated liver fibrosis in mice and decreased inflammatory cell infiltration. Furthermore, deficiency of MyD88 in macrophages inhibits the secretion of CXC motif chemokine 2 (CXCL2), which restrains the activation of HSCs characterized by NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation. Moreover, targeting CXCL2 by CXCR2 inhibitors attenuated the activation of HSCs and reduced liver fibrosis. Thus, MyD88 may represent a potential candidate target for the prevention and treatment of liver fibrosis.