Kir4.1-mediated immunophenotypic OPCs underlies sevoflurane-induced hypomyelination in the developing brain

Abstract

Clinical and animal experimental studies demonstrate that prolonged or repeated general anesthesia (GA) impairs myelination in the developing brain. However, the underlying cellular mechanisms remain unclear. Oligodendrocyte precursor cells (OPCs), as the primary source cells to myelination, have recently been shown to undergo immunomodulatory properties, leading to inhibition of OPCs differentiation in neurological disorders. It remains unknown whether the neuroinflammatory OPCs is involved in sevoflurane-induced hypomyelination. Here, we investigated the effects of sevoflurane on phenotype of OPCs and myelination in neonatal rats. Our findings showed that sevoflurane altered OPCs by inducing the expression of major histocompatibility complex class I (MHC-I) and MHC-II and increased the levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-6. This process affected OPC differentiation into mature oligodendrocytes, ultimately leading to demyelination and motor coordination impairments. Mechanistically, sevoflurane reduced the expression of Kir4.1 in OPCs. In vitro experiments demonstrated that the expression of MHC-I/MHC-II and the levels of pro-inflammatory cytokines were significantly elevated in Kir4.1-deficient OPCs, and meanwhile, the differentiation of these cells was impaired. These findings clarify the critical role of Kir4.1 in OPC-mediated immunomodulatory crosstalk, while revealing novel therapeutic targets for preventing anesthesia-induced neurotoxicity in the developing brain.