Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but may regulate neurorepair processes after experimental ischemic stroke

Lemarchand, Eloïse and Grayston, Alba and Wong, Raymond and Rogers, Miyako and Ouvrier, Blake and Llewellyn, Benjamin and Webb, Freddie and Lénárt, Nikolett and Dénes, Ádám and Brough, David and Allan, Stuart M and Bix, Gregory J and Pinteaux, Emmanuel (2025) Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but may regulate neurorepair processes after experimental ischemic stroke. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 45 (8). pp. 1479-1492. ISSN 0271-678X

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Abstract

Inflammation is a key contributor to stroke pathogenesis and exacerbates brain damage leading to poor outcome. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. However, the distinct roles of the two major IL-1 receptor type 1 agonists, IL-1α and IL-1β, and the specific role of IL-1α in ischemic stroke remain largely unknown. Here we show that IL-1α and IL-1β have different spatio-temporal expression profiles in the brain after experimental stroke, with early microglial IL-1α expression (4 h) and delayed IL-1β expression in infiltrated neutrophils and a small microglial subset (24–72 h). We examined for the first time the specific role of microglial-derived IL-1α in experimental permanent and transient ischemic stroke through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1α deletion did not influence acute outcome after ischemic stroke. However, microglial IL-1α knock out (KO) mice showed reduced peri-infarct vessel density and reactive astrogliosis at 14 days post-stroke, alongside long-term impaired functional recovery. Our study identifies for the first time a critical role for microglial IL-1α on post-stroke neurorepair and recovery, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop effective therapies.

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