Work

IL-33 confers neuroprotection by activating the ST2/PPAR-γ signaling axis in microglia following subarachnoid in male mice

Year: 2025

Type: article

Abstract: BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe cerebrovascular event often associated with high mortality and significant neurological impairment. Neuroinflammation is a hallmark of early brain injury (EBI), which substantially determines clinical outcomes. Interleukin-33 (IL-33) is a cytokine within the IL-1 family, known to regulate inflammatory and immune reactions through binding to its specific receptor, suppression of tumorigenicity 2 (ST2). This study focuses on clarifying how IL-33/ST2 signaling participates in the pathophysiological process following SAH in male mice.. METHODS: A mouse model of SAH was induced by prechiasmatic cistern injection. These mice received prophylactic administration of recombinant IL-33. Neurological function, brain edema, neuronal apoptosis, and neuroinflammation were comprehensively evaluated. Additionally, in vitro experiments using BV2 microglial cells were conducted to elucidate the mechanism. Furthermore, protein sequencing was carried out to delineate potential mechanistic pathways. RESULTS: IL-33 treatment significantly improved neurological function, reduced brain edema, and attenuated neuronal death after SAH. Mechanistically, IL-33 shifted microglial polarization from the detrimental M1 phenotype towards a protective state, thereby decreasing intracellular ROS levels and supporting mitochondrial metabolic activity, resulting in reduced cellular stress. This protective effect appeared to be mediated via the PPAR-γ pathway, as inhibition of this pathway with GW9662 attenuated the beneficial effects of IL-33. CONCLUSION: Our findings demonstrate that IL-33 confers robust neuroprotection against SAH-induced early brain injury by modulating microglial polarization via the PPAR-γ pathway. This positions the IL-33/ST2 axis as a promising novel immunomodulatory strategy for the treatment of SAH.

Source: Journal of Stroke and Cerebrovascular Diseases

DOI: 10.1016/j.jstrokecerebrovasdis.2025.108503