Remote Ischemic Postconditioning Attenuates Neuroinflammation and Suggests a Potential Benefit for Early Neurological Recovery after Subarachnoid Hemorrhage via the IL-9/JAK2-STAT5 Signaling Pathway.

Abstract

Subarachnoid hemorrhage (SAH) often leads to cognitive impairment, in which neuroinflammation plays a pivotal role. While remote ischemic postconditioning (RIPostC) has demonstrated neuroprotective potential, its clinical efficacy and underlying mechanisms remain incompletely defined. This study identified interleukin-9 (IL-9) as a key mediator of RIPostC's effects through an integrated clinical and basic research approach. In a prospective proof-of-concept clinical trial, RIPostC was associated with improved early neurological recovery and significantly upregulated serum IL-9 levels in SAH patients. It suggests a potential clinical benefit that warrants further validation. Using a murine SAH model, results showed RIPostC improved cognitive function, suppressed pro-inflammatory cytokines (IL-1β, IL-6), and elevated anti-inflammatory cytokines (IL-9, IL-10). Mechanistically, RIPostC activated the JAK2/STAT5 signaling pathway. Immunofluorescence revealed specific expression of the IL-9 receptor (IL-9R) on microglia. In vitro experiments using BV2 microglial cells confirmed that IL-9 directly promotes microglial polarization towards an anti-inflammatory M2 phenotype and enhances IL-10 production via the JAK2/STAT5 pathway. Collectively, these preliminary findings suggest that RIPostC alleviates neuroinflammation and cognitive impairment after SAH, a process mechanistically linked to the upregulation of IL-9 and subsequent activation of the JAK2/STAT5 pathway in microglia. This study positions IL-9 as a promising therapeutic target for SAH.