ST2/IL-33-dependent microglial response limits acute ischemic brain injury

Abstract

ST2, amemberoftheinterleukin (IL)1receptorfamily,anditsligandIL-33playcritical roles in immune regulation and inflammatory responses. This study explores the roles of endogenous IL-33/ST2 signaling in ischemic brain injury and elucidates the underlying mechanisms of action. The expression of IL-33 rapidly increased in oligodendrocytes and astrocytes after 60 min transient middle cerebral artery occlusion (tMCAO). ST2 receptor deficiency exacerbated brain infarction 3 d after tMCAO as well as distal permanent MCAO. ST2 deficiency also aggravated neurological deficitsupto7dafter tMCAO.Conversely, intracerebroventricular infusions of IL-33 after tMCAO at tenuated brain infarction.Flow cytometry analyses demonstrated high levels of ST2 expression on microglia, and this expression was dramatically enhanced after tMCAO. The absence of ST2 enhanced sthe expression of M1 polarization marker sonmicroglia/macrophages,and impaired the expression of M2 polarization markers after tMCAO. In vitro studies on various types of cultures and coculture systems confirmed that IL-33/ST2 signaling potentiated expression of IL-10 and other M2 genes in primary microglia. The activation of ST2 on microglia led to a protective phenotype that enhanced neuronal survival against oxygen glucose deprivation. Further in vitro studies revealed that IL-33-activated microglia released IL-10, and that this was critical for their neuroprotective effects. Similarly, intracerebroventricular infusions of IL-33 into IL-10knock-outmicefailed to provide neuroprotection against tMCAO in vivo. These results shednewlight on the IL-33/ST2 axis as an immuneregulatory mechanism that serves as a natural brake on the progression of ischemic brain injury.