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

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.