Mosoian Arevik, Zhang Lumin, Hong Feng, Cunyat Francesc, Rahman Adeeb, Bhalla Riti, Panchal Ankur, Saiman Yedidya, Fiel M Isabel, Florman Sander, Roayaie Sasan, Schwartz Myron, Branch Andrea, Stevenson Mario, Bansal Meena B
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA.
J Leukoc Biol. 2017 May;101(5):1083-1090. doi: 10.1189/jlb.3HI0516-242R. Epub 2016 Dec 16.
End-stage liver disease is a common cause of non-AIDS-related mortality in HIV patients, despite effective anti-retroviral therapies (ARTs). HIV-1 infection causes gut CD4 depletion and is thought to contribute to increased gut permeability, bacterial translocation, and immune activation. Microbial products drain from the gut into the liver via the portal vein where Kupffer cells (KCs), the resident liver macrophage, clear translocated microbial products. As bacterial translocation is implicated in fibrogenesis in HIV patients through unclear mechanisms, we tested the hypothesis that HIV infection of KCs alters their response to LPS in a TLR4-dependent manner. We showed that HIV-1 productively infected KCs, enhanced cell-surface TLR4 and CD14 expression, and increased IL-6 and TNF-α expression, which was blocked by a small molecule TLR4 inhibitor. Our study demonstrated that HIV infection sensitizes KCs to the proinflammatory effects of LPS in a TLR4-dependent manner. These findings suggest that HIV-1-infected KCs and their dysregulated innate immune response to LPS may play a role in hepatic inflammation and fibrosis and represent a novel target for therapy.
尽管有有效的抗逆转录病毒疗法（ARTs），终末期肝病仍是HIV患者非艾滋病相关死亡的常见原因。HIV-1感染导致肠道CD4细胞耗竭，并被认为会导致肠道通透性增加、细菌易位和免疫激活。微生物产物通过门静脉从肠道排入肝脏，在那里，肝脏常驻巨噬细胞库普弗细胞（KCs）清除易位的微生物产物。由于细菌易位通过不明机制与HIV患者的纤维化形成有关，我们检验了这样一个假设，即KCs的HIV感染以TLR4依赖的方式改变其对LPS的反应。我们发现HIV-1能有效感染KCs，增强细胞表面TLR4和CD14表达，并增加IL-6和TNF-α表达，而小分子TLR4抑制剂可阻断这种增加。我们的研究表明，HIV感染以TLR4依赖的方式使KCs对LPS的促炎作用敏感。这些发现表明，HIV-1感染的KCs及其对LPS失调的固有免疫反应可能在肝脏炎症和纤维化中起作用，并代表了一个新的治疗靶点。
