Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
J Biol Chem. 2013 May 10;288(19):13610-9. doi: 10.1074/jbc.M112.381046. Epub 2013 Mar 28.
HIV-1 infection causes chronic neuroinflammation in the central nervous system (CNS).
The spinal cytokine up-regulation induced by HIV-1 gp120 protein depends on Wnt5a/CaMKII and/or Wnt5a/JNK pathways.
gp120 stimulates cytokine expression in the spinal cord dorsal horn by activating Wnt5a signaling.
The finding reveals Wnt signaling-mediated novel mechanisms by which HIV-1 may cause neuroinflammation. Chronic expression of pro-inflammatory cytokines critically contributes to the pathogenesis of HIV-associated neurological disorders (HANDs), but the host mechanism that regulates the HIV-induced cytokine expression in the CNS remains elusive. Here, we present evidence for a crucial role of Wnt5a signaling in the expression of pro-inflammatory cytokines in the spinal cord induced by a major HIV-envelope protein, gp120. Wnt5a is mainly expressed in spinal neurons, and rapidly up-regulated by intrathecal injection (i.t.) of gp120. We show that inhibition of Wnt5a by specific antagonists blocks gp120-induced up-regulation of IL-1β, IL-6, and TNF-α in the spinal cord. Conversely, injection (i.t.) of purified recombinant Wnt5a stimulates the expression of these cytokines. To elucidate the role of the Wnt5a-regulated signaling pathways in gp120-induced cytokine expression, we have focused on CaMKII and JNKs, the well characterized down-stream targets of Wnt5a signaling. We find that Wnt5a is required for gp120 to activate CaMKII and JNK signaling. Furthermore, we demonstrate that the Wnt5a/CaMKII pathway is critical for the gp120-induced expression of IL-1β, whereas the Wnt5a/JNK pathway is for TNF-α expression. Meanwhile, the expression of IL-6 is co-regulated by both pathways. These results collectively suggest that Wnt5a signaling cascades play a crucial role in the regulation of gp120-induced expression of pro-inflammatory cytokines in the CNS.
HIV-1 感染会导致中枢神经系统（CNS）的慢性神经炎症。
HIV-1 gp120 蛋白诱导的脊髓细胞因子上调依赖于 Wnt5a/CaMKII 和/或 Wnt5a/JNK 途径。
gp120 通过激活 Wnt5a 信号刺激脊髓背角细胞因子的表达。
该发现揭示了 HIV-1 可能引起神经炎症的 Wnt 信号转导介导的新机制。促炎细胞因子的慢性表达是 HIV 相关神经障碍（HANDs）发病机制的关键，但调节中枢神经系统中 HIV 诱导的细胞因子表达的宿主机制仍不清楚。在这里，我们提供了证据表明，Wnt5a 信号在主要 HIV 包膜蛋白 gp120 诱导的脊髓中促炎细胞因子的表达中起关键作用。Wnt5a 主要在脊髓神经元中表达，并通过鞘内注射（i.t.）gp120 迅速上调。我们表明，特异性拮抗剂抑制 Wnt5a 可阻断 gp120 诱导的脊髓中 IL-1β、IL-6 和 TNF-α的上调。相反，纯化的重组 Wnt5a 注射（i.t.）刺激这些细胞因子的表达。为了阐明 Wnt5a 调节的信号通路在 gp120 诱导的细胞因子表达中的作用，我们专注于 CaMKII 和 JNKs，这是 Wnt5a 信号的典型下游靶标。我们发现 Wnt5a 是 gp120 激活 CaMKII 和 JNK 信号所必需的。此外，我们证明 Wnt5a/CaMKII 途径对于 gp120 诱导的 IL-1β表达至关重要，而 Wnt5a/JNK 途径对于 TNF-α 表达至关重要。同时，IL-6 的表达受这两条途径共同调节。这些结果共同表明，Wnt5a 信号级联在调节中枢神经系统中 gp120 诱导的促炎细胞因子表达中起着至关重要的作用。
