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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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S1P2 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, 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 occlu ...[more]

PMID: 31431671

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Project description:BackgroundThe pathogenic roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling in cerebral ischemia have been evidenced mainly through the efficacy of FTY720 that binds non-selectively to four of the five S1P receptors (S1P1,3,4,5). Recently, S1P1 and S1P2 were identified as specific receptor subtypes that contribute to brain injury in cerebral ischemia; however, the possible involvement of other S1P receptors remains unknown. S1P3 can be the candidate because of its upregulation in the ischemic brain, which was addressed in this study, along with underlying pathogenic mechanisms.MethodsWe used transient middle cerebral artery occlusion/reperfusion (tMCAO), a mouse model of transient focal cerebral ischemia. To identify S1P3 as a pathogenic factor in cerebral ischemia, we employed a specific S1P3 antagonist, CAY10444. Brain damages were assessed by brain infarction, neurological score, and neurodegeneration. Histological assessment was carried out to determine microglial activation, morphological transformation, and proliferation. M1/M2 polarization and relevant signaling pathways were determined by biochemical and immunohistochemical analysis.ResultsInhibiting S1P3 immediately after reperfusion with CAY10444 significantly reduced tMCAO-induced brain infarction, neurological deficit, and neurodegeneration. When S1P3 activity was inhibited, the number of activated microglia was markedly decreased in both the periischemic and ischemic core regions in the ischemic brain 1 and 3 days following tMCAO. Moreover, inhibiting S1P3 significantly restored the microglial shape from amoeboid to ramified microglia in the ischemic core region 3 days after tMCAO, and it attenuated microglial proliferation in the ischemic brain. In addition to these changes, S1P3 signaling influenced the proinflammatory M1 polarization, but not M2. The S1P3-dependent regulation of M1 polarization was clearly shown in activated microglia, which was affirmed by determining the in vivo activation of microglial NF-?B signaling that is responsible for M1 and in vitro expression levels of proinflammatory cytokines in activated microglia. As downstream effector pathways in an ischemic brain, S1P3 influenced phosphorylation of ERK1/2, p38 MAPK, and Akt.ConclusionsThis study identified S1P3 as a pathogenic mediator in an ischemic brain along with underlying mechanisms, involving its modulation of microglial activation and M1 polarization, further suggesting that S1P3 can be a therapeutic target for cerebral ischemia.

Dataset Information

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

Publications

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

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