S1P(1) Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia
- Authors
- Gaire, Bhakta Prasad; Bae, Young Joo; Choi, Ji Woong
- Issue Date
- Nov-2019
- Publisher
- KOREAN SOC APPLIED PHARMACOLOGY
- Keywords
- Transient middle cerebral artery occlusion (tMCAO); S1P(1); AUY954; M1/M2 polarization; Microglia
- Citation
- BIOMOLECULES & THERAPEUTICS, v.27, no.6, pp.522 - 529
- Journal Title
- BIOMOLECULES & THERAPEUTICS
- Volume
- 27
- Number
- 6
- Start Page
- 522
- End Page
- 529
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/893
- DOI
- 10.4062/biomolther.2019.005
- ISSN
- 1976-9148
- Abstract
- M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor sub-type 1 (S1P(1)) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P(1) and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P(1) is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P(1) was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P(1) activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P(1) activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-kappa B activation in post-ischemic brain. Particularly, NF-kappa B activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P(1) in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P(1) activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P(1) could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P(1 )activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevantAkt, all of which were downstream pathways following SIP, activation. Overall, these results revealed S1P(1)-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.
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