巨噬细胞中的 MyD88 通过激活 HSCs 中的 NLRP3 炎性小体增强肝纤维化。
MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs.
机构信息
National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning 530021, China.
College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
出版信息
Int J Mol Sci. 2021 Nov 17;22(22):12413. 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.
由肝星状细胞（HSCs）激活介导的慢性肝脏疾病导致肝纤维化。Toll 样受体（TLR）信号传导的信号衔接子 MyD88 参与肝纤维化的进展。然而，MyD88 在肝纤维化中骨髓细胞中的具体作用尚未得到彻底研究。在这项研究中，我们使用了四氯化碳（CCl）诱导的小鼠纤维化模型，其中骨髓细胞中的 MyD88 被选择性耗尽。骨髓细胞中 MyD88 的缺乏减轻了小鼠的肝纤维化并减少了炎症细胞浸润。此外，巨噬细胞中 MyD88 的缺乏抑制趋化因子 CXC 基序 2（CXCL2）的分泌，从而抑制 NLR 家族富含吡啶结构域蛋白 3（NLRP3）炎性体激活的 HSCs 的激活。此外，通过 CXCR2 抑制剂靶向 CXCL2 可减弱 HSCs 的激活并减少肝纤维化。因此，MyD88 可能是预防和治疗肝纤维化的潜在候选靶标。
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