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-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.
BACKGROUND:HIV-1 infection causes chronic neuroinflammation in the central nervous system (CNS). RESULTS: The spinal cytokine up-regulation induced by HIV-1gp120 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-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.
Authors: Lisa C Loram; Jacqueline A Harrison; Lindsey Chao; Frederick R Taylor; Anireddy Reddy; Carissa L Travis; Rona Giffard; Yousef Al-Abed; Kevin Tracey; Steven F Maier; Linda R Watkins Journal: Brain Behav Immun Date: 2010-03-28 Impact factor: 7.217
Authors: Hsin-Yi Henry Ho; Michael W Susman; Jay B Bikoff; Yun Kyoung Ryu; Andrea M Jonas; Linda Hu; Rejji Kuruvilla; Michael Eldon Greenberg Journal: Proc Natl Acad Sci U S A Date: 2012-02-17 Impact factor: 11.205
Authors: Joachim Reischl; Susanne Schwenke; Johanna M Beekman; Ulrich Mrowietz; Steffen Stürzebecher; Jürgen F Heubach Journal: J Invest Dermatol Date: 2006-07-20 Impact factor: 8.551
Authors: Jean-Pierre Louboutin; Beverly A S Reyes; Lokesh Agrawal; Elisabeth J Van Bockstaele; David S Strayer Journal: Eur J Neurosci Date: 2011-11-17 Impact factor: 3.386
Authors: Mark A Christman; Douglas J Goetz; Eric Dickerson; Kelly D McCall; Christopher J Lewis; Fabian Benencia; Mitchell J Silver; Leonard D Kohn; Ramiro Malgor Journal: Am J Physiol Heart Circ Physiol Date: 2008-05-02 Impact factor: 4.733
Authors: Adelina Holguin; Kevin A O'Connor; Joseph Biedenkapp; Jay Campisi; Julie Wieseler-Frank; Erin D Milligan; Michael K Hansen; Leah Spataro; Elena Maksimova; Courtenay Bravmann; David Martin; Monika Fleshner; Steven F Maier; Linda R Watkins Journal: Pain Date: 2004-08 Impact factor: 6.961