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.
Zhu Y, Zeng B, et al. • Translational stroke research • 2026
Remote ischemic postconditioning alleviates neuroinflammation and cognitive impairment after subarachnoid hemorrhage through upregulation of IL-9 and subsequent activation of the JAK2/STAT5 pathway in microglia, positioning IL-9 as a promising therapeutic target for SAH.
Key Findings
Results
RIPostC was associated with improved early neurological recovery in SAH patients in a prospective proof-of-concept clinical trial.
The study used an integrated clinical and basic research approach combining a prospective proof-of-concept clinical trial with murine model experiments.
The authors explicitly note this 'suggests a potential clinical benefit that warrants further validation,' indicating preliminary rather than definitive findings.
Clinical improvement was observed in early neurological recovery outcomes following RIPostC treatment.
Results
RIPostC significantly upregulated serum IL-9 levels in SAH patients.
Serum IL-9 was identified as a key mediator of RIPostC's effects through the integrated clinical and basic research approach.
IL-9 upregulation was observed in both the clinical trial patients and the murine SAH model.
The finding positions IL-9 as a biomarker of RIPostC's neuroprotective activity in the clinical setting.
Results
RIPostC improved cognitive function and modulated cytokine profiles in a murine SAH model.
RIPostC suppressed pro-inflammatory cytokines IL-1β and IL-6 in the murine SAH model.
RIPostC elevated anti-inflammatory cytokines IL-9 and IL-10 in the murine SAH model.
Cognitive function improvement was demonstrated in the mouse model following RIPostC treatment.
Results
RIPostC activated the JAK2/STAT5 signaling pathway in the context of SAH.
Mechanistic analysis revealed that RIPostC's anti-inflammatory effects were linked to JAK2/STAT5 pathway activation.
The JAK2/STAT5 pathway was identified as a downstream mediator of IL-9 signaling following RIPostC.
This mechanistic link was identified through experiments in both the murine SAH model and in vitro BV2 microglial cell experiments.
Results
The IL-9 receptor (IL-9R) is specifically expressed on microglia in the brain.
Immunofluorescence was used to identify the cellular localization of IL-9R.
IL-9R expression was found specifically on microglia, indicating these cells are the primary target of IL-9 signaling in this context.
This finding establishes the cellular mechanism by which systemic or local IL-9 upregulation translates to microglial modulation.
Results
IL-9 directly promotes microglial polarization toward an anti-inflammatory M2 phenotype via the JAK2/STAT5 pathway.
In vitro experiments were conducted using BV2 microglial cells to confirm direct effects of IL-9.
IL-9 treatment enhanced IL-10 production in BV2 microglial cells.
The promotion of M2 polarization and IL-10 production was confirmed to occur via the JAK2/STAT5 pathway.
These in vitro findings corroborated the in vivo mechanistic findings from the murine SAH model.
Conclusions
IL-9 is identified as a key mediator of RIPostC's neuroprotective effects and a promising therapeutic target for SAH.
The study used an integrated approach combining clinical trial data with murine model and in vitro experiments to identify IL-9's role.
IL-9's role spans from RIPostC-induced upregulation to microglial M2 polarization to suppression of neuroinflammation and cognitive protection.
The authors describe these as 'preliminary findings,' acknowledging limitations in the clinical proof-of-concept design.
IL-9 is positioned as both a potential biomarker and a direct therapeutic target for SAH-related neuroinflammation.
What This Means
This research suggests that a non-invasive technique called remote ischemic postconditioning (RIPostC) — which involves briefly cutting off and restoring blood flow to a limb (like the arm) after a brain bleed — may help protect the brain following a subarachnoid hemorrhage (SAH), a type of stroke caused by bleeding around the brain. In a small clinical trial, SAH patients who received RIPostC showed signs of better early neurological recovery and had higher blood levels of a protein called interleukin-9 (IL-9) compared to those who did not receive the treatment. The authors caution that this is a preliminary, proof-of-concept finding that needs further validation in larger studies.
To understand how RIPostC works, the researchers also studied mice with SAH and brain cells in the laboratory. They found that RIPostC reduced harmful inflammation in the brain, improved memory and cognitive function in mice, and shifted the balance of immune signaling proteins toward an anti-inflammatory state. Specifically, RIPostC raised levels of IL-9 and IL-10 (anti-inflammatory proteins) while lowering levels of IL-1β and IL-6 (pro-inflammatory proteins). The study pinpointed that IL-9 works by binding to receptors found on microglia — the brain's resident immune cells — and activating a cellular signaling chain called JAK2/STAT5, which instructs the microglia to adopt a protective, anti-inflammatory behavior.
This research matters because subarachnoid hemorrhage is a devastating condition that frequently causes lasting cognitive problems, and there are currently very few treatments proven to reduce brain inflammation after such bleeds. These findings suggest that RIPostC — a simple, low-risk procedure — may reduce this inflammation through a specific biological pathway involving IL-9, and that IL-9 itself could potentially be developed as a direct treatment target. However, because this is an early-stage proof-of-concept study combining animal experiments with a small clinical trial, much larger and more rigorous human trials will be needed before any clinical recommendations could be made.
Zhu Y, Zeng B, Huang Z, Wen D, Li X, Liang F, et al.. (2026). 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.. Translational stroke research. https://doi.org/10.1007/s12975-026-01455-4