Microglial hyperactivation mediated by sphingosine kinase 1/sphingosine-1-phosphate (SphK1/S1P) signalling and the consequent inflammatory mediator production serve as the key drivers of cerebral ischaemia-reperfusion injury (CIRI). Although SphK1 reportedly controls autophagy and microglial activation, it remains uncertain as to whether SphK1 is similarly capable of regulating damage mediated by CIRI-activated microglia. In the current study, we adopted both in vitro oxygen-glucose deprivation reperfusion (OGDR) models and in vivo rat models of focal CIRI to ascertain this possibility. It was found that CIRI upregulated SphK1 and induced autophagy in microglia, while inhibiting these changes significantly impaired to prevented neuronal apoptosis. Results of mechanistic investigation revealed that SphK1 promoted autophagy via the tumour necrosis factor receptor associated factor 2 (TRAF2) pathway. Altogether, our findings unfolded to reveal a novel mechanism, whereby SphK1-induced autophagy in microglia contributed to the pathogenesis of CIRI, potentially highlighting novel avenues for future therapeutic intervention in ischaemic stroke patients.
Keywords: autophagy; cerebral ischaemia-reperfusion; microglia; neuroinflammation; sphingosine kinase 1; sphingosine-1-phosphate.
© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.