Cyclophilin D knockdown/knockout promotes microglia M2 polarization by inhibiting STAT1 to alleviate neuroinflammation in neonatal white matter injury.

The activation of microglia cells is intimately associated with the pathophysiology of neuroinflammation and neonatal white matter injury (WMI). Cyclophilin D (CypD), a matrix cyclophilin, is known to be one of the important regulators of mitochondrial permeability transition pore. Currently, CypD has been discovered the function of regulating inflammation. However, its impact on microglia in the context of neonatal WMI remains unclear. In our study, CypD inhibition ameliorated microglia activation, decreased pro-inflammatory factor levels, and increased anti-inflammatory factor levels in both neonatal WMI mice and oxygen glucose deprivation/reperfusion (OGD/R)-induced BV2 microglial cells. CypD knockout promoted myelination and rescued neurological function in mice following hypoxic-ischemic injury. In addition, CypD knockdown alleviated mitochondrial dysfunction of BV2 microglial cells. RNA-Seq indicated that CypD inhibition downregulated STAT1. Western blotting results verified that CypD inhibition significantly downregulated the phosphorylation level of STAT1. Our research revealed the protective role of CypD inhibition in neuroinflammation and mitochondrial function of microglia. Targeting CypD expression in microglia may be a potential therapeutic option for neonatal WMI.