TREM2 Promotes Liver Fibrosis by Enhancing Hepatic Stellate Cell Endocytosis and Activation via Phosphorylating ITGAV

作者全名："Liu, Yi; Que, Ke-ting; Yang, Peng-fei; Bai, Jie; Qiu, Chan; Yu, Hui-hong; Ning, Bo; He, Song; Deng, Liang; Zhong, Li"

作者地址："[Liu, Yi; Qiu, Chan; Yu, Hui-hong; Ning, Bo; He, Song; Zhong, Li] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400010, Peoples R China; [Que, Ke-ting] Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing 400010, Peoples R China; [Yang, Peng-fei] Chongqing Med Univ, Affiliated Hosp 2, Dept Nephrol, Chongqing 400010, Peoples R China; [Bai, Jie] Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing 400016, Peoples R China; [Deng, Liang] Chongqing Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Chongqing, Peoples R China"

通信作者："Zhong, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400010, Peoples R China."

来源：JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001050758400001

JCR分区：Q4

影响因子：0.8

年份：2023

卷号：37

期号：7

开始页：3693

结束页：3704

文献类型：Article

关键词：hepatic fibrosis; hepatic stellate cells; TREM2; ITGAV

摘要："Objective: This study aims to explore the role of the triggering receptor expressed on myeloid cells 2 (TREM2) in liver fibrosis and the activation of hepatic stellate cells (HSCs). Methods: Tandem Mass Tag (TMT) proteomic analysis, immunohistochemical staining and immunofluorescence were conducted to examine the variations of TREM2 expression between healthy and fibrotic liver tissues. Sh-TREM2 adenovirus was delivered into the mouse portal vein, and a chronic liver fibrosis model was developed by injecting carbon tetrachloride (CCl4). The expression of TREM2 in liver tissues was evaluated using immunohistochemistry and immunofluorescence staining. Next, primary mouse HSCs were extracted, and the TREM2 expression in cells was knocked down by adenovirus. Primary HSCs were exposed to transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor-BB (PDGF-BB), or epidermal growth factor (EGF) to observe the effects of cytokines on cells. The cells were incubated for 2 h in spleen tyrosine kinase (Syk) inhibitor R406 and serine/threonine-protein kinase (AKT) 1 inhibitor A-674563, and Western blot was used to detect the phosphorylation integrin alpha v (ITGAV) protein expression. Results: TREM2 expression was significantly increased in human liver fibrosis tissue. TREM2 knockdown markedly reduced liver fibrosis in the mouse fibrosis model. In addition, TREM2 knockdown affected the phagosome signal pathway. TREM2 knockdown failed to activate HSCs by cytokines, which could inhibit endocytosis and TGF-beta signaling without impacting the TGF receptor. Interestingly, the integrin family (ITGAV, integrin alpha x (ITGAX) and integrin alpha 4 (ITGA4)), especially ITGAV expression, decreased after the knockdown of TREM2. The overexpression or knockdown of TREM2 promoted or inhibited ITGAV and phosphorylation ITGAV protein expression, respectively. R406 treatment considerably reduced the phosphorylation ITGAV protein expression of HSCs compared to the control and A-674563 treatment groups. Conclusions: TREM2 phosphorylated ITGAV via Syk, which boosted the endocytosis of cytokines to aggravate liver fibrosis."

基金机构："National Natu-ral Science Foundation of China [82000583]; Natural Science Foundation of Chongqing, China [cstc2020jcyj-msxmX0214, cstc2020jcyj-msxmX0703]"

基金资助正文："Funding This study was supported by the National Natu-ral Science Foundation of China (Grant No. 82000583) and the Natural Science Foundation of Chongqing, China (Grant No. (cstc2020jcyj-msxmX0214 and cstc2020jcyj-msxmX0703) ) ."