Wingless-type mammary tumor virus integration site family, member 5A (Wnt5a) regulates human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120)-induced expression of pro-inflammatory cytokines via the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and c-Jun N-terminal kinase (JNK) signaling pathways.

ABSTRACT

BACKGROUND: HIV-1 infection causes chronic neuroinflammation in the central nervous system (CNS). RESULTS: The spinal cytokine up-regulation induced by HIV-1 gp120 protein depends on Wnt5a/CaMKII and/or Wnt5a/JNK pathways. CONCLUSION: gp120 stimulates cytokine expression in the spinal cord dorsal horn by activating Wnt5a signaling. SIGNIFICANCE: 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-1ß, 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-1ß, 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.