INVESTIGATING THE DISTINCT SPATIOTEMPORAL ROLES OF INTERLEUKIN-1Α AND INTERLEUKIN-1Β DURING CHRONIC STROKE

Interleukin-1 (IL-1) is a key mediator of stroke pathogenesis and comprises two isoforms, IL-1α and IL-1β, which both signal through IL-1 receptor type 1 but have distinct spatiotemporal profiles. As stroke survivors frequently develop chronic immune-driven comorbidities, defining the long-term roles of these isoforms is increasingly important, particularly alongside ongoing IL-1 receptor antagonist clinical trials. Previous work from our laboratory using a permanent MCAO model demonstrated rapid microglial (Iba1⁺) IL-1α upregulation at 4h post-stroke that declined by 24–72h, whereas IL-1β expression was delayed and limited to a small subset of microglia and infiltrating immune cells. Using a transient MCAO model in male and female mice, we recently found that IL-1α expression remains elevated within infarcted tissue from 28–56 days compared with non-infarcted regions. IL-1α localises to subsets of microglia and lipid-laden foam cells (Iba1⁺BODIPY⁺), suggesting a role in sustained inflammatory responses. To investigate cell-specific functions, we generated tamoxifen-inducible microglia-specific IL-1α and IL-1β knockout mice. Microglial IL-1α deletion reduced densities of Iba1⁺ and IL-1α⁺Iba1⁺ foam cells at 14 days post-stroke, persisting at 42 days, but was associated with worsened neurological deficits, indicating a role in foam-cell formation and chronic injury progression. In contrast, microglial IL-1β deletion improved acute neurological outcome with little impact on long-term recovery, although it enhanced subventricular zone neurogenesis and ectopic neuroblast migration while reducing hippocampal neurogenesis. These findings demonstrate distinct, non-redundant roles for microglial IL-1α and IL-1β in ischaemic brain injury and recovery, guiding development of isoform-specific therapeutic strategies.