Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
J Immunol. 2012 Apr 15;188(8):3876-85. doi: 10.4049/jimmunol.1103024. Epub 2012 Mar 9.
HIV-associated neurologic disorders are a mounting problem despite the advent of highly active antiretroviral therapy. To address mechanisms of HIV-associated neurologic disorders, we used an SIV pigtailed macaque model to study innate immune responses in brain that suppress viral replication during acute infection. We previously reported that during acute infection in brain, noncanonical type I IFN signaling occurs, where IFN-β mRNA is induced while IFN-α is simultaneously suppressed. Two downstream IFN-stimulated genes, MxA and TRAIL, also show differential expression patterns. In this study, we show that differential signaling is due to interactions between macrophages and astrocytes. Astrocytes produce high levels of CCL2 upon SIV infection, which binds to CCR2 receptors on macrophages, leading to a selective suppression of IFN-α and the IFN-stimulated gene TRAIL while simultaneously inducing IFN-β and MxA. The interactions between chemokine and cytokine pathways are a novel finding that may specifically occur in the CNS.
尽管高效抗逆转录病毒疗法已经问世，但与 HIV 相关的神经紊乱仍是一个日益严重的问题。为了研究与 HIV 相关的神经紊乱的发病机制，我们使用 SIV 卷尾猴模型研究了急性感染期间抑制病毒复制的大脑固有免疫反应。我们之前的研究报告表明，在大脑的急性感染期间，会发生非典型的 I 型 IFN 信号通路，其中 IFN-β mRNA 被诱导，同时 IFN-α 被同时抑制。两种下游的 IFN 刺激基因 MxA 和 TRAIL 也表现出不同的表达模式。在这项研究中，我们表明，差异信号是由于巨噬细胞和星形胶质细胞之间的相互作用引起的。星形胶质细胞在 SIV 感染后会产生高水平的 CCL2，它与巨噬细胞上的 CCR2 受体结合，导致 IFN-α和 IFN 刺激基因 TRAIL 的选择性抑制，同时诱导 IFN-β 和 MxA。趋化因子和细胞因子途径之间的相互作用是一个新的发现，它可能专门发生在中枢神经系统中。
