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Objective: Intracerebral hemorrhage (ICH) is a devastating medical condition that remains a leading cause of death and long term disability in the US. Hematoma triggers a cascade of signaling events resulting in secondary brain injury and severe neurological deficits. Microglia and macrophage are activated within minutes after ICH, which may influence stroke outcome by clearing the hematoma and regulating neuro-inflammation. However, the molecular mechanism underlying the functional regulation of microglia and macrophages in ICH is poorly understood. The current study was designed to test the role of signal transducers and activators of transcription 6 (STAT6) in microglia/macrophage functions in a mouse model of ICH.Methods: Male adult WT and STAT6 KO mice were subjected to intrastriatal collagenase (0.075U) injection. Spatial and temporal profiles of STAT6 activation after ICH were determined by double-label immunostaining of phospho-STAT6 and cell markers. Neurobehavioral performances were assessed using rotarod, foot fault and water maze tests up to day 21 after ICH. Gray and white matter injury was examined quantitatively on sections stained with antibodies against MAP2/NeuN and MBP, respectively. Microglial phagocytosis of fluorescent labeled-red blood cells was evaluated in vitro by immunofluorescence and flow cytometry.Results: Robustly enhanced expression of phospho-STAT6 was found predominantly in Iba1+ cells, starting at day 1, peaking at day 5, and lasting for at least 14 d after ICH. STAT6 KO mice exhibited exacerbated sensorimotor and spatial learning and memory deficits compared to WT mice (P<0.05). STAT6 KO mice also showed larger neuronal tissue loss and more severe white matter injury (P<0.01). Hematoma resolving was slower in STAT6 KO mice than WT mice (P=0.03). In cultures, primary microglia derived from STAT6 KO mice had 52.6% reduction of phagocytic activity compared to WT microglia (P=0.006).Conclusions: STAT6 is activated in microglia/macrophage after ICH and plays a critical role in ameliorating gray and white matter injury and facilitating post-stroke neurological recovery. STAT6-afforded neuroprotection against ICH may be attributable, at least in part, to the enhanced hematoma clearance by phagocytes.