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

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 activat...

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Bibliographic Details
Published in:The European journal of neuroscience 2022-08, Vol.56 (4), p.4287-4303
Main Authors: Zeng, Yuanyuan, Zhang, Wei, Xue, Tengteng, Zhang, Dayong, Lv, Manhua, Jiang, Yongjia
Format: Article
Language:English
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
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Summary: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.
ISSN:0953-816X
1460-9568
DOI:10.1111/ejn.15749