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

Eloise Lemarchand, Alba Grayston, Raymond Wong, Miyako Rogers, Blake Ouvrier, Benjamin Llewellyn, Freddie Webb, David Brough, Stuart Allan, Gregory Bix, Emmanuel Pinteaux

Research output: Working paperPreprint

Abstract

Inflammation is a key contributor to stroke pathogenesis and drives exacerbated brain damage leading to poor outcomes in patients. 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. IL-1α and IL-1β are the two major IL-1 type 1 receptor (IL-1R1) agonists from the IL-1 family, and although the role of IL-1β in stroke has been extensively studied, the distinct roles of both isoforms, and particularly that of IL-1α, remains largely unknown. Here we show that IL-1α and IL-1β have different spatio-temporal expression profiles in the brain after experimental stroke, with an early IL-1α microglial expression (4 h post-stroke) and delayed IL-1β expression in infiltrated neutrophils and a small (10%) microglial subset (24-72 h post-stroke). Using cell-specific deletion of IL-1α through tamoxifen-inducible Cre-loxP-mediated recombination, we examined the specific contribution of microglial-derived IL-1α in mouse models of permanent and transient ischemic stroke. Selective microglial IL-1α deletion did not influence brain damage, cerebral blood flow, IL-1β expression, neutrophil infiltration, microglial nor endothelial activation up to 24 h 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 a worse functional recovery compared to wild-type (WT) mice. RNA sequencing analysis and subsequent pathway analysis on ipsilateral/contralateral cortex 4 h after stroke revealed a downregulation of the neuronal CREB signaling pathway in microglial IL-1α KO compared to WT mice. Our study identifies for the first time a critical role for microglial IL-1α in the regulation of neuronal activity, neurorepair and functional recovery after stroke, highlighting the importance of selectively targeting specific IL-1 mechanisms in brain injury to develop more effective therapies.
Original languageEnglish
PublisherCold Spring Harbor Laboratory Press
DOIs
Publication statusPublished - 21 Feb 2024

Publication series

NamebioRxiv
PublisherCold Spring Harbor Laboratory Press
ISSN (Print)2692-8205

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