Abstract TP21: The Role Of Interleukin-1α Cytokine In Poststroke Inflammation

Abstract

Stroke remains the second leading cause of death globally, with a total of 5.5 million deaths in 2016 and an estimated global lifetime risk of stroke for those aged 25 years or older at 24.9%. A key feature of stroke and poststroke injury is the inflammatory response, which is driven by a variety of pro-inflammatory cytokines to include interleukin-1 (IL-1). Evidence from pre-clinical studies have demonstrated a deleterious effect of IL-1 poststroke with a beneficial effect observed after blocking IL-1 in both pre-clinical and clinical settings. The IL-1 family has both IL-1β and IL-1α forms, and although IL-1β has been most closely studied, the distinct roles of both IL-1 isoforms during poststroke inflammation is largely unknown. In this study, we examined the contribution of IL-1α in ischemic stroke. We characterized the spatio-temporal effect of IL-1 in the brain after stroke using an in vivo model of middle cerebral artery thrombosis in an inducible IL-1α knockout mouse through topical application of FeCl3. We found that IL-1α precedes IL-1β expression after ischemic stroke and is restricted to microglia whereas IL-1β is expressed by both neutrophils and microglia. Intriguingly, microglial IL-1α deletion does not influence brain damage after ischemic stroke, and furthermore does not influence cerebral blood flow or neutrophil infiltration and IL-1β expression up to 24h after ischemic stroke. Pathway analysis following RNAseq suggests that microglial IL-1α regulates neuronal activity through CREB signaling. In vitro studies in Neuro2a (N2a) murine cell line additionally show neuronal activity regulation through CREB signaling via microglial IL-1α after oxygen glucose deprivation and reperfusion (OGD/R) model of stroke. As the role of IL-1α in stroke has yet to be fully elucidated, future experiments using both murine and in vitro models will clarify the role that IL-1α has in the pathogenesis of stroke and its relevance to inflammatory features posttroke, which may lead to future therapeutic insight.