| Title: |
Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke |
| Authors: |
Lemarchand, Eloise; Grayston, Alba; Wong, Raymond; Rogers, Miyako; Ouvrier, Blake; Llewellyn, Benjamin; Webb, Freddie; Brough, David; Allan, Stuart; Bix, Gregory; Pinteaux, Emmanuel |
| Source: |
Lemarchand, E, Grayston, A, Wong, R, Rogers, M, Ouvrier, B, Llewellyn, B, Webb, F, Brough, D, Allan, S, Bix, G & Pinteaux, E 2024 'Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke' bioRxiv, Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/2024.02.16.580635 |
| Publisher Information: |
Cold Spring Harbor Laboratory Press |
| Publication Year: |
2024 |
| Collection: |
The University of Manchester: Research Explorer - Publications |
| Description: |
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. |
| Document Type: |
report |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/38585834 |
| DOI: |
10.1101/2024.02.16.580635 |
| Availability: |
https://research.manchester.ac.uk/en/publications/ed450266-3ed3-462a-a367-f013e8ddeac5; https://doi.org/10.1101/2024.02.16.580635 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.EA89E307 |
| Database: |
BASE |