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

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-κB 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1323-1) contains supplementary material, which is available to authorized users.

Modulators of microglia activation and polarization in ischemic stroke (Review)

“…S1P is the ligand for S1PR and has been identified to bind to S1PR1, S1PR2 and S1PR3 to trigger neuroinflammatory responses in ischemic stroke (Fig. 2) (89)(90)(91). an in vitro study reported that upon the addition of S1P to the culture medium of primary microglia, the expression levels of IL-17 were increased (31).…”

“…This culminated in an increase in the expression levels of S1P and M1 microglial markers, CD11b, cd16, cd32, cd86, TnF-α and il-1β, as well as an increased infarct volume and neurological deficit (81). CAY10444, an inhibitor of S1Pr3, and PF-543, an inhibitor of Sphk1, were identified to partially reverse the result to increase the expression levels (31,91); however, Qin et al (71) described opposing results, following the observation that Fingolimod, an S1Pr agonist, inhibited M1 microglia-induced neuroinflammation and shift microglia toward M2 polarization through regulating STaT3 signaling in a BcaS-induced model of ischemic stroke. Therefore, additional studies are required to determine the role of S1P and S1Prs in the regulation of microglia polarization following ischemic stroke.…”

Kellerin alleviates cognitive impairment in mice after ischemic stroke by multiple mechanisms

“…The effect of kellerin on the NLRP3 signaling pathway may be responsible for its function in regulating microglial polarization. MAPK signaling pathways also mediate microglial polarization during cerebral ischemia (Gaire, Bae, & Choi, ; Gaire, Song, & Choi, ; Xiang et al, ). MAPKs function as three‐tiered kinase cascades leading to the activation of the effector kinases ERK, p38, and JNK (Kondreddy et al, ; Lanna et al, ).…”

Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks

“…S1P signaling in TAMs leads to increased cellular proliferation, and enhanced production of different pro-inflammatory cytokines (such as TNF-α and IL-1β and IL-17) and nitric oxide, and this signaling is inhibited by SphK1 inhibition or gene knockout of this enzyme [149,253]. S1P1-3 receptor subtypes were identified as relevant in S1P signaling in transient cerebral ischemia [253][254][255][256]. In addition, S1P regulates M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.…”