Dataset Information

Sphingosine 1-phosphate receptor subtype 3 (S1P₃) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

ABSTRACT:

Background

The 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 (S1P_1,3,4,5). 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.

Methods

We 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.

Results

Inhibiting 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.

Conclusions

This 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.

SUBMITTER: Gaire BP

PROVIDER: S-EPMC6180378 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Sphingosine 1-phosphate receptor subtype 3 (S1P<sub>3</sub>) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

Gaire Bhakta Prasad BP Song Mi-Ryoung MR Choi Ji Woong JW

Journal of neuroinflammation 20181010 1

<h4>Background</h4>The 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 (S1P<sub>1,3,4,5</sub>). Recently, S1P<sub>1</sub> and S1P<sub>2</sub> were identified as specific receptor subtypes that contribute to brain injury in cerebral ischemia; however, the possible involvement of other S1P receptors remains unknown. S1P<sub>3</sub ...[more]

PMID: 30305119

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Dataset Information

Sphingosine 1-phosphate receptor subtype 3 (S1P₃) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

Background

Methods

Results

Conclusions

Publications

Sphingosine 1-phosphate receptor subtype 3 (S1P<sub>3</sub>) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

Background

Methods

Results

Conclusions

Publications

Sphingosine 1-phosphate receptor subtype 3 (S1P<sub>3</sub>) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sphingosine 1-phosphate receptor subtype 3 (S1P₃) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization.