MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization |
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| Authors: | Jie Zhang Yu Liu Haiqiang Chen Qi Yuan Jinyan Wang Meng Niu Lingling Hou Jianchun Gu Jinhua Zhang |
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| Institution: | 1.The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, P.R. China ;2.Department of Immunology, Basic School of Medicine, China Medical University, Shenyang, P. R. China ;3.Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, P. R. China ;4.Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China |
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| Abstract: | During liver fibrosis, quiescent HSCs (qHSCs) are activated to become activated HSCs (aHSCs)/myofibroblasts. The signal adapter MyD88, an essential component of TLR signaling, plays an important role in liver fibrosis. However, far less is known about the specific effects of MyD88 signaling in both qHSCs and aHSCs in the progress of liver fibrosis. Here, we used a CCl4-induced mouse fibrosis model in which MyD88 was selectively depleted in qHSCs (GFAPMyD88−/− mice) or aHSCs (α-SMAMyD88−/− mice). MyD88 deficiency in qHSCs or aHSCs attenuated liver fibrosis in mice and inhibited α-SMA-positive cell activation. Inhibition of MyD88 in HSCs decreased α-SMA and collagen I levels, inflammatory cell infiltration, and pro-inflammatory gene expression. Furthermore, MyD88 signaling in HSCs increased the secretion of CXCL10, which promoted macrophage M1 polarization through CXCR3, leading to activation of the JAK/STAT1 pathway. Inhibition of CXCL10 attenuated macrophage M1 polarization and reduced liver fibrosis. Thus, MyD88 signaling in HSCs crucially contributes to liver fibrosis and provides a promising therapeutic target for the prevention and treatment of liver fibrosis.Subject terms: Mechanisms of disease, Kupffer cells |
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