Semaphorin 3A-Plexin-A1 signaling through ERK activation is crucial for Toll-like receptor-induced NO production in BV-2 microglial cells

Ito,Takuji; Morita,Tokiko; Yoshida,Kenji; Negishi,Takayuki; Yukawa,Kazunori

doi:10.3892/ijmm.2014.1727

Semaphorin 3A-Plexin-A1 signaling through ERK activation is crucial for Toll-like receptor-induced NO production in BV-2 microglial cells

Authors:
- Takuji Ito
- Tokiko Morita
- Kenji Yoshida
- Takayuki Negishi
- Kazunori Yukawa
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Affiliations: Department of Physiology, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan
Published online on: April 4, 2014 https://doi.org/10.3892/ijmm.2014.1727
Pages: 1635-1642

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Abstract

Semaphorin family members have been identified as axonal guidance molecules that mediate the directional determination for axonal elongation during neuronal development. Several semaphorins have been shown to play crucial roles for various immune response phases. In a previous study using knockout mice, we suggested that Plexin-A1, a Semaphorin 3A (Sema3A) receptor, is involved in the increased production of inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the murine microglial response to lipopolysaccharide (LPS). In that study, Sema3A-Plexin-A1 signaling was also shown to have crosstalk with Toll-like receptor 4 (TLR4) signaling to increase nitric oxide production, although the specific intracellular signaling molecule involved in the NO increase was not identified. By investigating the role of Plexin-A1 in the response of the BV-2 microglial cell line to LPS, in the present study novel findings regarding the influence of Plexin-A1 activation on TLR4 signaling in microglial cells were investigated. First, the production of inflammatory markers such as inducible nitric oxide synthase (iNOS), IL-1β and TNF-α in the response to TLR4 stimulation was significantly decreased in BV-2 cells with the knockdown of Plexin-A1. Accordingly, Plexin-A1 was required for the enhanced production of inflammatory factors induced by LPS in BV-2 microglial cells. Second, Plexin-A1 signaling in BV-2 cells showed crosstalk with the LPS-induced TLR4 pathway through activation of nuclear factor-κB (NF-κB) and extracellular signal‑regulated kinase (ERK). Third, LPS-induced NO production in BV-2 cells was intensified by Sema3A-Plexin-A1 signaling in an ERK1/2 activation-dependent manner. This finding suggested the crucial role of Plexin-A1 signaling through ERK activation in TLR4 activation-induced NO production in BV-2 microglial cells. These results therefore suggest that Plexin-A1 and Sema3A are possible new targets for treating LPS-induced encephalopathy and neuroinflammation-related mental disorders.

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