S1P₁ Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia

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.

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

“…In opposition to S1P 2 , pathogenic mechanisms of S1P 1 and S1P 3 in cerebral ischemia rely on microglial activation [239,240]. Moreover, the same group elucidated the importance of S1P 1 -regulation in promoting a pro-inflammatory M1 polarization of astrocytes, which was brought about by the intracellular signal transducers ERK1/2, p38, and JNK MAPK favoring brain damage after cerebral ischemia [241]. Furthermore, Zamanian et al, examined reactive astrogliosis in response to either MCAO or LPS and showed Pentraxin-related protein PTX3 (PTX3), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A), and S1P 3 to be markers of reactive astrocytes after MCAO [242].…”

Immunoreactive Cells After Cerebral Ischemia

“…Specifically, S1P1 activation influences mitogen-activated protein kinases and phosphoinositide 3-kinase/Akt activation in the ischemic hemisphere, and those pathways can increase M1 polarization while simultaneously decreasing M2 polarization. The influence is especially significant on microglia M1 polarization (122). These results may lead to further study of S1P subtypes on their relationships with and regulation of the M1/M2 polarization of microglia.…”

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, ).…”