Sphingosine kinase 1 promotes cerebral ischemia‐reperfusion injury through inducing ER stress and activating the NF‐κB signaling pathway

Abstract

Endoplasm reticulum stress and inflammation response have been found to be linked to cerebral ischemia-reperfusion (IR) injury. Sphingosine kinase 1 (SPHK1) has been reported to be a novel endoplasm reticulum regulator. The aim of our study is to figure out the role of SPHK1 in cerebral IR injury and verify whether it has an ability to regulate inflammation and endoplasm reticulum stress. Hydrogen peroxide was used to induce cerebral IR injury. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, western blots, and immunofluorescence were used to measure the alterations of cell viability, inflammation response, and endoplasm reticulum stress. The results demonstrated that after exposure to hydrogen peroxide, cell viability was reduced whereas SPHK1 expression was significantly elevated.Knockdown of SPHK1 attenuated hydrogen peroxide-mediated cell death and reversed cell viability. Our data also demonstrated that SPHK1 deletion reduced endoplasm reticulum stress and alleviated inflammation response in hydrogen peroxide-treated cells. In addition, we also found that SHPK1 modulated endoplasm reticulum stress and inflammation response to through the NF-κB signaling pathway.Inhibition of NF-κB signaling pathway has similar results when compared with the cells with SPHK1 deletion. Altogether, our results demonstrated that SPHK1 upregulation, induced by hydrogen peroxide, is responsible for cerebral IR injury through inducing endoplasm reticulum stress and inflammation response in a manner working through the NF-κB signaling pathway. This finding provides new insight into the molecular mechanism to explain the neuron death induced by cerebral IR injury.

The role of sphingolipids in endoplasmic reticulum stress

“…The role of S1P generation in ER stress is controversial and appears to depend on the specific SphK isoform. SphK1, which is induced by hydrogen peroxide, is linked to cerebral ischaemia-reperfusion injury via the induction of ER stress and activation of the nuclear factor kappa B (NF-jB) signalling pathway [78]. In contrast, a SphK1 deficiency alleviated acetaminophen-induced ER stress by altering the phosphorylation of IRE1a and PERK-eIF2a, levels of ATF4 and activation of ATF6 [79].…”

Inhibition of SphK1/S1P Signaling Pathway Alleviates Fibrosis and Inflammation of Rat Myocardium after Myocardial Infarction

“…In addition, SphK1/S1P was found to mediate the inhibitory effect of resveratrol on lung tissue remodeling [ 9 ]. In cerebral ischemia-reperfusion injury, SphK1/S1P was found to aggravate the injury by inducing endoplasmic reticulum stress and activating the NF- κ B signaling pathway [ 10 ]. However, there were few studies on the effect of SphK1/S1P on MI.…”

Effects of spike protein and toxin-like peptides found in COVID-19 patients on human 3D neuronal/glial model undergoing differentiation: Possible implications for SARS-CoV-2 impact on brain development

“…SPHK1 is known to control cell survival, migration and inflammation [85] , [86] , and its deregulation has been observed in various inflammatory and immune related-diseases, such as hypertension, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, rheumatoid arthritis, and asthma [87] , [88] , [89] . It is also known to regulate microglial phagocytosis [88] , and to modulate inflammation during cerebral ischemia/reperfusion injury [90] , [91] . Moreover, SPHK1/S1PR2 signaling axis is closely associated with the course of Temporal Lobe Epilepsy [92] .…”