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S1P2 contributes to microglial activation and M1 polarization following cerebral ischemia through ERK1/2 and JNK.


ABSTRACT: Sphingosine 1-phosphate (S1P) signaling has emerged as a drug target in cerebral ischemia. Among S1P receptors, S1P2 was recently identified to mediate ischemic brain injury. But, pathogenic mechanisms are not fully identified, particularly in view of microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed whether microglial activation is the pathogenesis of S1P2-mediated brain injury in mice challenged with transient middle cerebral artery occlusion (tMCAO). To suppress S1P2 activity, its specific antagonist, JTE013 was given orally to mice immediately after reperfusion. JTE013 administration reduced the number of activated microglia and reversed their morphology from amoeboid to ramified microglia in post-ischemic brain after tMCAO challenge, along with attenuated microglial proliferation. Moreover, JTE013 administration attenuated M1 polarization in post-ischemic brain. This S1P2-directed M1 polarization appeared to occur in activated microglia, which was evidenced upon JTE013 exposure in vivo as suppressed M1-relevant NF-?B activation in activated microglia of post-ischemic brain. Moreover, JTE013 exposure or S1P2 knockdown reduced expression levels of M1 markers in vitro in lipopolysaccharide-driven M1 microglia. Additionally, suppressing S1P2 activity attenuated activation of M1-relevant ERK1/2 and JNK in post-ischemic brain or lipopolysaccharide-driven M1 microglia. Overall, our study demonstrated that S1P2 regulated microglial activation and M1 polarization in post-ischemic brain.

SUBMITTER: Sapkota A 

PROVIDER: S-EPMC6702157 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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S1P<sub>2</sub> contributes to microglial activation and M1 polarization following cerebral ischemia through ERK1/2 and JNK.

Sapkota Arjun A   Gaire Bhakta Prasad BP   Kang Min-Gu MG   Choi Ji Woong JW  

Scientific reports 20190820 1


Sphingosine 1-phosphate (S1P) signaling has emerged as a drug target in cerebral ischemia. Among S1P receptors, S1P<sub>2</sub> was recently identified to mediate ischemic brain injury. But, pathogenic mechanisms are not fully identified, particularly in view of microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed whether microglial activation is the pathogenesis of S1P<sub>2</sub>-mediated brain injury in mice challenged with transient middle cerebral artery occlu  ...[more]

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