Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tissue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (MΦ) are major players of inflammatory responses in the post-TBI brain and possess high functional heterogeneity. However, the plasticity of these cells has yet to be exploited to develop
therapies that can mitigate
brain inflammation and improve the outcome after TBI. This study investigated the
transcription factor STAT1 as a key determinant of proinflammatory Mi/MΦ responses and aimed to develop STAT1 as a novel therapeutic target for TBI using a controlled cortical impact model of TBI on adult male mice. TBI induced robust upregulation of STAT1 in the brain at the subacute injury stage, which occurred primarily in Mi/MΦ. Intraperitoneal administration of
fludarabine, a selective STAT1 inhibitor, markedly alleviated proinflammatory Mi/MΦ responses and
brain inflammation burden after TBI. Such phenotype-modulating effects of
fludarabine on post-TBI Mi/MΦ were reproduced by
tamoxifen-induced, selective knockout of STAT1 in Mi/MΦ (STAT1 mKO). By propelling Mi/MΦ away from a detrimental proinflammatory phenotype, STAT1 mKO was sufficient to reduce long-term neurological deficits and brain lesion size after TBI. Importantly, short-term
fludarabine treatment after TBI elicited long-lasting improvement of TBI outcomes, but this effect was lost on STAT1 mKO mice. Together, our study provided the first line of evidence that STAT1 causatively determines the proinflammatory phenotype of brain Mi/MΦ after TBI. We also showed promising preclinical data supporting the use of
fludarabine as a novel immunomodulating
therapy to TBI.SIGNIFICANCE STATEMENTThe functional phenotype of microglia and macrophages (Mi/MΦ) critically influences
brain inflammation and the outcome after
traumatic brain injury (TBI); however, no
therapies have been developed to modulate Mi/MΦ functions to treat TBI. Here we report for the first time that the
transcription factor STAT1 is a key mediator of proinflammatory Mi/MΦ responses in the post-TBI brain, the specific deletion of which ameliorates
neuroinflammation and improves long-term functional recovery after TBI. We also show excellent efficacy of a selective STAT1 inhibitor
fludarabine against TBI-induced functional deficits and
brain injury using a mouse model, presenting STAT1 as a promising therapeutic target for TBI.