Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke.

Lemarchand, E.; Grayston, A.; Wong, R.; Rogers, M.; Ouvrier, B.; Llewellyn, B.; Webb, F.; Brough, D.; Allan, S. M.; Bix, G.; Pinteaux, E.

doi:10.1101/2024.02.16.580635

bioRxiv · 10.1101/2024.02.16.580635

Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke.

Lemarchand, E.·Grayston, A.·Wong, R.·Rogers, M.·Ouvrier, B.·Llewellyn, B.·Webb, F.·Brough, D.·Allan, S. M.·Bix, G.·Pinteaux, E.

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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-1 and IL-1{beta}, and the specific role of IL-1 in ischemic stroke remain largely unknown. Here we show that IL-1 and IL-1{beta} have different spatio-temporal expression profiles in the brain after experimental stroke, with early microglial IL-1 expression (4 h) and delayed IL-1{beta} 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-1 in experimental permanent and transient ischemic stroke through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1 deletion did not influence acute brain damage, cerebral blood flow, IL-1{beta} expression, neutrophil infiltration, microglial nor endothelial activation after ischemic stroke. However, microglial IL-1 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-1 on neurorepair and functional recovery after stroke, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop more effective therapies.

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Lemarchand, E., Grayston, A., Wong, R., Rogers, M., Ouvrier, B., Llewellyn, B., Webb, F., Brough, D., Allan, S. M., Bix, G., Pinteaux, E.. 2024-02-21. Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke.. https://doi.org/10.1101/2024.02.16.580635

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