S1P₁ Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia
10.4062/biomolther.2019.005
- Author:
Bhakta Prasad GAIRE
1
;
Young Joo BAE
;
Ji Woong CHOI
Author Information
1. College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea. pharmchoi@gachon.ac.kr
- Publication Type:Original Article
- Keywords:
Transient middle cerebral artery occlusion (tMCAO);
S1P₁;
AUY954;
M1/M2 polarization;
Microglia
- MeSH:
Brain Injuries;
Brain Ischemia;
Brain;
Infarction, Middle Cerebral Artery;
Microglia;
Phosphorylation;
RNA, Messenger;
Sphingosine;
Up-Regulation
- From:Biomolecules & Therapeutics
2019;27(6):522-529
- CountryRepublic of Korea
- Language:English
-
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 subtype 1 (S1P₁) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P₁ and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P₁ is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P₁ was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P₁ 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 S1P₁ activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P₁ in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P₁ activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P₁ could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P₁ activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P₁ activation. Overall, these results revealed S1P₁-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.
