The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury

Abstract

Abstract JOURNAL/nrgr/04.03/01300535-202405000-00038/inline-graphic1/v/2023-09-28T063346Z/r/image-tiff We previously showed that hydrogen sulfide (H2S) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of H2S in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a H2S precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine β synthase (a major H2S synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine β synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring β-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.