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

Abstract Inflammation is a key contributor to stroke pathogenesis and drives exacerbated 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. IL-1α and IL-1β are the two major IL-1 type 1 receptor (IL-1R1) agonists from the IL-1 family. The distinct roles of both isoforms, and particularly that of IL-1α, 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 the specific contribution of microglial-derived IL-1α in experimental permanent and transient ischemic stroke through cell-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1α deletion did not influence acute brain damage, cerebral blood flow, IL-1β expression, neutrophil infiltration, microglial nor endothelial activation 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. 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 on neuronal activity, neurorepair and functional recovery after stroke, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop more effective therapies..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 27. März Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:	Lemarchand, Eloise [VerfasserIn] Grayston, Alba [VerfasserIn] Wong, Raymond [VerfasserIn] Rogers, Miyako [VerfasserIn] Ouvrier, Blake [VerfasserIn] Llewellyn, Benjamin [VerfasserIn] Webb, Freddie [VerfasserIn] Lénárt, Nikolett [VerfasserIn] Denes, Adam [VerfasserIn] Brough, David [VerfasserIn] Allan, Stuart M [VerfasserIn] Bix, Gregory [VerfasserIn] Pinteaux, Emmanuel [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2024.02.16.580635

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PPN (Katalog-ID):	XBI042642094