Interleukin-1 beta promotes neuronal differentiation through the Wnt5a/RhoA/JNK pathway in cortical neural precursor cells

Abstract

Pro-inflammatory cytokine interleukin-1 beta (IL-1β) is a key mediator of inflammation and stress in the central nervous system (CNS), and is highly expressed in the developing brain. In this study, we investigated the possible role of IL-1β in neuronal differentiation of cortical neural precursor cells (NPCs). We showed that stimulation with IL-1β increased expression levels of neurotrophin-3 (NT3) and neurogenin 1 (Ngn1) and promoted neurite outgrowth. We also found that IL-1β increased mRNA and protein levels of Wnt5a. Knockdown of Wnt5a by transfection with Wnt5a siRNA inhibited IL-1β-induced neuronal differentiation. Moreover, IL-1β-induced Wnt5a expression was regulated by nuclear factor kappa B (NF-κB) activation, which is involved in IL-1β-mediated neuronal differentiation. To examine the role of Wnt5a in neuronal differentiation of NPCs, we exogenously added Wnt5a. We found that exogenous Wnt5a promotes neuronal differentiation, and activates the RhoA/Rho-associated kinase (ROCK)/c-jun N-terminal kinase (JNK) pathway. In addition, Wnt5a-induced neuronal differentiation was blocked by RhoA siRNA, as well as by a specific Rho-kinase inhibitor (Y27632) or a SAPK/JNK inhibitor (SP600125). Furthermore, treatment with RhoA siRNA, Y27632, or SP600125 suppressed the IL-1β-induced neuronal differentiation. Therefore, these results suggest that the sequential Wnt5a/RhoA/ROCK/JNK pathway is involved in IL-1β-induced neuronal differentiation of NPCs.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0383-6) contains supplementary material, which is available to authorized users.

Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

“…On the contrary, inhibition of the component of the noncanonical Wnt/PCP signaling JNK did not prevent neuronal differentiation induced by Wnt5a. Although the Wnt5a/JNK pathway has been involved in neuronal differentiation during embryonic development, our data are in agreement with a previous study showing that knockdown of FZD3 or Celsr1‐3, components of Wnt/PCP pathway, had no effect on neuronal differentiation of newborn cells in the adult dentate gyrus . These evidences suggest that Wnt/PCP pathway is not involved in neuronal differentiation during adult hippocampal neurogenesis, indicating that as shown before, adult NPCs behave differently to embryonic NPCs, having a differential response to Wnt5a/JNK signaling.…”

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency

“…It should be noted, however, that neither Wnt5a nor p-MYPT expression increased until administration of an HS diet in aged WT and KL-KO mice, suggesting that salt is needed for activation of the Wnt5a/RhoA pathway. Accumulating evidence indicates that inflammatory cytokines including IL-1β and IL-17 are involved in salt-sensitive hypertension (10), and that IL-1β activates RhoA/ ROCK through upregulation of Wnt5a expression (66). Interestingly, HS increases salt and water storage in the interstitial compartment associated with increased TPR in salt-sensitive hypertensive patients, suggesting increased interstitial salt/water storage may relate to vascular dysfunction in salt-sensitive hypertension (67); notably, salt accumulation in muscle and skin increases with age (68).…”

Establishment of an a priori protocol for the implementation and interpretation of an in‐vitro testing battery for the assessment of developmental neurotoxicity

“…In addition, narciclasine interacts with the translation elongation factor eEF1A and increases Rho activity. These signaling pathways lead to alteration of migration, neurite growth or neuronal differentiation (Fürst 2016;Park et al 2018;Threadgill et al 1997). Exactly these effects were found in the phenotypic screening of the DNT in vitro battery showing its high predictive capacity.…”