Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
FASEB J. 2010 Jul;24(7):2292-300. doi: 10.1096/fj.09-143503. Epub 2010 Feb 24.
MicroRNA-mediated regulation of gene expression appears to be involved in a variety of cellular processes, including development, differentiation, proliferation, and apoptosis. Mir-146a is thought to be involved in the regulation of the innate immune response, and its expression is increased in tissues associated with chronic inflammation. Among the predicted gene targets for mir-146a, the chemokine CCL8/MCP-2 is a ligand for the CCR5 chemokine receptor and a potent inhibitor of CD4/CCR5-mediated HIV-1 entry and replication. In the present study, we have analyzed changes in the expression of mir-146a in primary human fetal microglial cells upon infection with HIV-1 and found increased expression of mir-146a. We further show that CCL8/MCP-2 is a target for mir-146a in HIV-1 infected microglia, as overexpression of mir-146a prevented HIV-induced secretion of MCP-2 chemokine. The clinical relevance of our findings was evaluated in HIV-encephalitis (HIVE) brain samples in which decreased levels of MCP-2 and increased levels of mir-146a were observed, suggesting a role for mir-146a in the maintenance of HIV-mediated chronic inflammation of the brain.
微小 RNA 介导的基因表达调控似乎参与了多种细胞过程，包括发育、分化、增殖和凋亡。Mir-146a 被认为参与了先天免疫反应的调节，其在与慢性炎症相关的组织中表达增加。在 Mir-146a 的预测基因靶标中，趋化因子 CCL8/MCP-2 是 CCR5 趋化因子受体的配体，也是 CD4/CCR5 介导的 HIV-1 进入和复制的有效抑制剂。在本研究中，我们分析了 HIV-1 感染原代人胎儿小神经胶质细胞时 Mir-146a 的表达变化，发现 Mir-146a 的表达增加。我们进一步表明，CCL8/MCP-2 是 HIV-1 感染小神经胶质细胞中 Mir-146a 的靶标，因为 Mir-146a 的过表达可阻止 HIV 诱导的 MCP-2 趋化因子的分泌。在 HIV 脑炎 (HIVE) 脑样本中评估了我们发现的临床相关性，在这些样本中观察到 MCP-2 水平降低和 Mir-146a 水平升高，表明 Mir-146a 在维持 HIV 介导的大脑慢性炎症中起作用。
