KLF7 Blocks MKNK2/HIF-1 Pathway-Mediated M1 Microglia Polarization to Ameliorate Ischemic Stroke-Induced Neurological Injury

Background: Ischemic stroke (IS) is a common Neurological Disease with a significant financial burden but lacks effective drugs. This study sought to explore the mechanisms underlying MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2), a gene enriched in the hypoxia-inducible factor-1 (HIF-1) signaling, in IS-related neurological injury.

Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models were used in vivo and in vitro. Rats were infected with lentiviral vectors harboring knockdown or overexpression of the target genes, followed by MCAO/R to conduct 2,3,5-triphenyltetrazolium chloride, HE, Fluoro-Jade C, and TUNEL, enzyme-linked immunosorbent assay, immunohistochemistry, and neurological deficits assessment. The regulation of Krueppel-like factor 7 (KLF7) on MKNK2 was analyzed by ChIP and dual-luciferase assays. The effects of the KLF7/MKNK2/HIF-1 axis on the M1 or M2 polarization of rat microglia were demonstrated by the transfection of knockdown or overexpression plasmids into the cells.

Results: MCAO/R-treated rat brain tissues and OGD/R-treated rat microglia showed MKNK2 upregulation along with activation of the HIF-1 signaling, whereas KLF7 expression was downregulated. Knockdown of MKNK2 inhibited the HIF-1 signaling and M1 microglia polarization, whereas it promoted M2 polarization. KLF7 repressed the MKNK2 transcription, thereby achieving the same effect as the knockdown of MKNK2 in vitro, which was reversed by combined overexpression of MKNK2. Knockdown of MKNK2 or overexpression of KLF7 ameliorated MCAO/R-induced brain damage and neurological injury in rats. MKNK2 overexpression reversed the alleviating effect of KLF7 overexpression on pathological brain injury in rats.

Conclusion: Significant downregulation of KLF7 expression after IS exacerbated pathological brain damage through the MKNK2-mediated HIF-1 pathway.

HIF‐1 pathway; Ischemic stroke; KLF7; MKNK2; microglia.