Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy.
Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy.
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DOI：
10.1172/jci.insight.152738
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发表时间：
2022-07-08
期刊：
影响因子：
8
通讯作者：
Su, Lishan
中科院分区：
文献类型：
--
作者：
Ahodantin, James;Nio, Kouki;Funaki, Masaya;Zhai, Xuguang;Wilson, Eleanor;Kottilil, Shyamasundaran;Cheng, Liang;Li, Guangming;Su, Lishan
肝病已成为接受联合抗逆转录病毒疗法（cART）治疗的HIV-1（PLWH）感染者的主要健康问题。为了研究HIV-1感染和cART是否相互作用导致肝脏疾病，用来自人胎肝的祖细胞重建的人源化小鼠感染HIV-1并用cART治疗。我们在此报告了慢性HIV-1感染与cART诱导的人源化小鼠肝炎和肝纤维化，与肝脏中M2样巨噬细胞（M2 LM）积累、TGF-β升高和IFN信号转导相关。有趣的是，IFN-I和TGF-β在体外协同激活人肝星状细胞（HepSC）。在机制上，IFN-I增强了HepSC中TGF-β诱导的SMAD 2/3活化。最后，阻断IFN-I信号传导逆转了人源化小鼠中HIV/cART诱导的肝脏疾病。与HIV-1和cART的人源化小鼠中的发现一致，我们检测到PLWH血液标本中肝损伤标志物M2 LM和IFN信号转导标志物与健康个体相比升高。这些发现确定了HIV/cART诱导的肝脏疾病中的IFN-I/M2 LM/HepSC轴，并表明抑制IFN-I信号传导或M2 LM可能为治疗接受抗逆转录病毒治疗的PLWH中的HIV/cART相关肝脏疾病提供新的治疗策略。
Liver diseases have become a major comorbidity health concern for people living with HIV-1 (PLWH) treated with combination antiretroviral therapy (cART). To investigate if HIV-1 infection and cART interact to lead to liver diseases, humanized mice reconstituted with progenitor cells from human fetal livers were infected with HIV-1 and treated with cART. We report here that chronic HIV-1 infection with cART induced hepatitis and liver fibrosis in humanized mice, associated with accumulation of M2-like macrophages (M2LMs), elevated TGF-β, and IFN signaling in the liver. Interestingly, IFN-I and TGF-β cooperatively activated human hepatic stellate cells (HepSCs) in vitro. Mechanistically, IFN-I enhanced TGF-β–induced SMAD2/3 activation in HepSCs. Finally, blockade of IFN-I signaling reversed HIV/cART-induced liver diseases in humanized mice. Consistent with the findings in humanized mice with HIV-1 and cART, we detected elevated markers of liver injury, M2LMs, and of IFN signaling in blood specimens from PLWH compared with those of healthy individuals. These findings identify the IFN-I/M2LM/HepSC axis in HIV/cART-induced liver diseases and suggest that inhibiting IFN-I signaling or M2LM may provide a novel therapeutic strategy for treating HIV/cART-associated liver diseases in PLWH treated with antiretroviral therapy.
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