Sphk1‐induced autophagy in microglia promotes neuronal injury following cerebral ischaemia–reperfusion

• Published in: The European journal of neuroscience Vol. 56; no. 4; pp. 4287 - 4303
• Main Authors: Zeng, Yuanyuan, Zhang, Wei, Xue, Tengteng, Zhang, Dayong, Lv, Manhua, Jiang, Yongjia
• Format: Journal Article
• Language: English
• Published: Chichester Wiley Subscription Services, Inc 01.08.2022
• Subjects: Animal models; Apoptosis; Autophagy; cerebral ischaemia–reperfusion; Inflammation; Ischemia; Microglia; neuroinflammation; Reperfusion; Signal transduction; Sphingosine kinase; sphingosine kinase 1; sphingosine‐1‐phosphate; TRAF2 protein; Tumor necrosis factor; Tumors
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15749

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. During cerebral ischaemia–reperfusion injury, SphK1 expression is upregulated, and autophagy in microglia is induced. SphK1 promotes the autophagy of microglia and neuronal apoptosis via regulation of TRAF2, thus promoting neuronal injury.