Inhibition of IL-6 signaling with tocilizumab improves stroke outcomes in aged mice but requires sex-specific dosing

Hudobenko, J.; Lee, E. A.; Delevati Colpo, G.; Atadja, L.; Goodman, G.; Huang, S.; Couture, L. E.; Chauhan, A.; McCullough, L. D.

doi:10.64898/2026.05.01.722347

bioRxiv · 10.64898/2026.05.01.722347

Inhibition of IL-6 signaling with tocilizumab improves stroke outcomes in aged mice but requires sex-specific dosing

Hudobenko, J.·Lee, E. A.·Delevati Colpo, G.·Atadja, L.·Goodman, G.·Huang, S.·Couture, L. E.·Chauhan, A.·McCullough, L. D.

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Abstract

Post-stroke inflammation contributes to poor outcomes in both clinical and experimental studies. Interleukin-6 (IL-6) is a key inflammatory mediator in ischemic stroke, and higher circulating IL-6 levels are associated with greater stroke severity and worse clinical outcomes. Targeting IL-6 signaling therefore represents a potential therapeutic strategy. We tested whether inhibition of IL-6 signaling with the IL-6 receptor (IL-6R) blocking antibody tocilizumab (TCZ) improves recovery after experimental stroke. Aged mice (18-20 months) underwent 60 minutes of middle cerebral artery occlusion. TCZ (20 mg/kg) was administered 5 hours after ischemia onset, and behavioral outcomes were assessed weekly for 5 weeks. Delayed TCZ treatment improved long-term functional recovery in aged male mice but not in aged females. To explore this difference, we measured circulating soluble IL-6R (sIL-6R) levels in mice and patients with ischemic stroke. Females exhibited significantly higher post-stroke sIL-6R levels. Increasing the TCZ dose to 100 mg/kg restored efficacy in aged female mice and improved long-term outcomes. These findings support a role for IL-6R pathway modulation in improving recovery after experimental stroke and suggest that therapeutic response may differ by sex and target availability, potentially related to differences in circulating sIL-6R after ischemic injury.

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Hudobenko, J., Lee, E. A., Delevati Colpo, G., Atadja, L., Goodman, G., Huang, S., Couture, L. E., Chauhan, A., McCullough, L. D.. 2026-05-06. Inhibition of IL-6 signaling with tocilizumab improves stroke outcomes in aged mice but requires sex-specific dosing. https://doi.org/10.64898/2026.05.01.722347

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