TY - UNPB
T1 - Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke
AU - Lemarchand, Eloise
AU - Grayston, Alba
AU - Wong, Raymond
AU - Rogers, Miyako
AU - Ouvrier, Blake
AU - Llewellyn, Benjamin
AU - Webb, Freddie
AU - Brough, David
AU - Allan, Stuart
AU - Bix, Gregory
AU - Pinteaux, Emmanuel
PY - 2024/2/21
Y1 - 2024/2/21
N2 - 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.
AB - 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.
UR - http://dx.doi.org/10.1101/2024.02.16.580635
U2 - 10.1101/2024.02.16.580635
DO - 10.1101/2024.02.16.580635
M3 - Preprint
C2 - 38585834
T3 - bioRxiv
BT - Selective deletion of interleukin-1 alpha in microglia regulates neuronal activity and neurorepair processes after experimental ischemic stroke
PB - Cold Spring Harbor Laboratory Press
ER -