Microglial IL-6 receptor signaling differentially regulates long-term cognitive recovery after ischemic stroke in a sex-dependent manner

Interleukin-6 (IL-6) signaling plays complex and context-dependent roles following ischemic stroke. While elevated IL-6 levels are associated with worse clinical outcomes, experimental studies suggest both injurious and protective effects depending on signaling pathway. Microglia express the IL-6 receptor (IL-6R) and are key regulators of post-stroke neuroinflammation and repair; however, the specific contribution of microglial IL-6R signaling to long-term cognitive recovery and its potential sex-dependent effects remain unclear. Male and female microglia-specific IL-6R knockout (CX3CR1-CreERT2; IL-6R fl/fl ) treated with tamoxifen or vehicle underwent 60-minute transient middle cerebral artery occlusion. Cognitive performance was assessed longitudinally up to 45 days post-stroke using object location testing, novel object recognition, Barnes maze, open field, and nesting assays. Microglial phenotype and STAT3 signaling were evaluated at day 7 post-stroke by flow cytometry. Tissue loss, chronic gliosis, neuronal preservation (NeuN), immature neuronal populations (DCX), vascular remodeling, and white matter integrity were quantified at day 60. Acute neurological deficits, infarct area and tissue loss were comparable between genotypes in both sexes. In females, microglial IL-6R deletion was associated with improved cognitive performance, reduced chronic gliosis, increased NeuN + , increased DCX + immature neuronal populations, and improved white matter status at 60 days post-stroke ( p < 0.05). These changes were accompanied by increased microglial IL-6 expression, enhanced CD206 expression, and increased STAT3 phosphorylation during the subacute recovery phase ( p < 0.05). In contrast, in males, IL-6R deletion reduced microglial pSTAT3 and SOCS3 expression, altered vascular remodeling, and did not confer comparable sustained cognitive benefit. Microglial IL-6R deletion was associated with long-term post-stroke recovery in a sex-dependent manner. IL-6R deletion was associated with improved cognitive recovery, reduced gliosis, and higher NeuN cell counts in females, but not comparable functional benefit in males. These findings support biological sex as an important consideration for IL-6R-targeted therapeutic strategies.