Hepatocyte-Specific Triggering of Hepatic Stellate Cell Profibrotic Activation by Apoptotic Bodies: The Role of Hepatoma-Derived Growth Factor, HIV, and Ethanol.
Hepatocyte-Specific Triggering of Hepatic Stellate Cell Profibrotic Activation by Apoptotic Bodies: The Role of Hepatoma-Derived Growth Factor, HIV, and Ethanol.
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DOI：
10.3390/ijms24065346
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发表时间：
2023-03-10
影响因子：
5.6
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肝病是HIV感染的主要合并症之一。肝纤维化发展的风险是由酒精滥用加强。在我们以前的研究中，我们报道了暴露于HIV和乙醛的肝细胞发生显著的凋亡，并且肝星状细胞（HSC）吞噬凋亡小体（AB）增强了其促纤维化激活。然而，除了肝细胞，在相同条件下，AB可以从肝脏浸润免疫细胞产生。本研究的目的是探讨淋巴细胞衍生的AB是否像肝细胞衍生的AB一样强烈地触发HSC促纤维化激活。从用HIV+乙醛处理的Huh7.5-CYP 2 E1（RLW）细胞和Jurkat细胞产生AB，并与HSC共培养以诱导其促纤维化活化。通过蛋白质组学分析ABs货物。从RLW产生的AB，而不是从Jurkat细胞激活HSC中的纤维化基因。这是由AB货物中肝细胞特异性蛋白的表达驱动的。这些蛋白质之一是肝细胞衍生生长因子，其抑制减弱HSC的促纤维化活化。在仅用免疫细胞而非人肝细胞人源化的小鼠中，感染HIV并喂食乙醇，未观察到肝纤维化。我们得出结论，肝细胞来源的HIV+ AB促进HSC活化，这可能导致肝纤维化进展。
Liver disease is one of the leading comorbidities in HIV infection. The risk of liver fibrosis development is potentiated by alcohol abuse. In our previous studies, we reported that hepatocytes exposed to HIV and acetaldehyde undergo significant apoptosis, and the engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) potentiates their pro-fibrotic activation. However, in addition to hepatocytes, under the same conditions, ABs can be generated from liver-infiltrating immune cells. The goal of this study is to explore whether lymphocyte-derived ABs trigger HSC profibrotic activation as strongly as hepatocyte-derived ABs. ABs were generated from Huh7.5-CYP2E1 (RLW) cells and Jurkat cells treated with HIV+acetaldehyde and co-culture with HSC to induce their pro-fibrotic activation. ABs cargo was analyzed by proteomics. ABs generated from RLW, but not from Jurkat cells activated fibrogenic genes in HSC. This was driven by the expression of hepatocyte-specific proteins in ABs cargo. One of these proteins is Hepatocyte-Derived Growth Factor, for which suppression attenuates pro-fibrotic activation of HSC. In mice humanized with only immune cells but not human hepatocytes, infected with HIV and fed ethanol, liver fibrosis was not observed. We conclude that HIV+ABs of hepatocyte origin promote HSC activation, which potentially may lead to liver fibrosis progression.