Remote Ischemic Postconditioning (RIPostC) attenuates SAH neuroinflammation and improves recovery via IL-9/JAK2-STAT5 pathway.

Early brain injury following Subarachnoid Hemorrhage (SAH) frequently leads to significant cognitive impairment, with neuroinflammation playing a critical role in this pathology. Current therapeutic strategies often fall short in effectively mitigating this inflammatory response and improving long-term neurological outcomes. While Remote Ischemic Postconditioning (RIPostC) has shown promise in neuroprotection, its precise mechanisms and clinical utility in SAH-induced neuroinflammation remain largely undefined, representing a key gap in treatment understanding.

Researchers conducted an integrated study involving a prospective proof-of-concept clinical trial, a murine SAH model, and in vitro experiments. In the clinical trial, RIPostC was applied to SAH patients, with early neurological recovery and serum IL-9 levels as primary endpoints. For the preclinical arm, SAH was induced in mice, followed by RIPostC intervention, assessing cognitive function, pro-inflammatory cytokines (IL-1β, IL-6), and anti-inflammatory cytokines (IL-9, IL-10). Immunofluorescence was used to identify IL-9R expression. In vitro, BV2 microglial cells were treated with IL-9 to investigate microglial polarization and JAK2/STAT5 pathway activation.

In the clinical trial, RIPostC was associated with improved early neurological recovery in SAH patients and significantly upregulated serum IL-9 levels. In the murine SAH model, 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 confirmed specific expression of the IL-9R on microglia. In vitro experiments using BV2 microglial cells demonstrated that IL-9 directly promotes microglial polarization towards an anti-inflammatory M2 phenotype and enhances IL-10 production via the JAK2/STAT5 pathway.

These findings collectively suggest that RIPostC alleviates neuroinflammation and cognitive impairment after SAH through the upregulation of IL-9 and subsequent activation of the JAK2/STAT5 pathway in microglia.