The ISL1-WDR5-H3K4me3-STC1 axis attenuates cerebral ischemia-reperfusion injury.

Abstract

Cerebral ischemia-reperfusion injury (CIRI) usually has a high mortality and disability rate, and inflammatory stimulation is an important risk factor for CIRI. ISL LIM Homeobox 1 (ISL1) is involved in the regulation of inflammatory response, and its role in CIRI progression has not been reported. Here, we established an animal model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and found that ISL1 was up-regulated in the peri-infarct cortex of tMCAO/R mice (log2FC = 4.7, adj. p < 0.01) and improved neurological dysfunction and reduced infarct size. At the same time, we found that ISL1 suppressed the expression of proinflammatory markers in the peri-infarct cortex. Consistently, in an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced microglial HMC3 cell model, ISL1 overexpression significantly curtailed the inflammatory response, as evidenced by reduced iNOS and CD16/32 expression. Mechanistically, dual-luciferase and ChIP assays confirmed that ISL1 promotes the transcriptional activation of Stanniocalcin 1 (STC1) by enhancing H3K4me3 enrichment at its promoter region. Furthermore, GST pull-down analyses suggested that this transcriptional regulation is likely mediated through the physical interaction between ISL1 and WDR5, which may recruit the MLL complex to facilitate H3K4me3 deposition. Collectively, our findings indicate that the ISL1-WDR5-H3K4me3 axis contributes to the upregulation of STC1, thereby attenuating neuroinflammation and CIRI-induced brain injury.