STAT1 Contributes to Microglial/Macrophage Inflammation and Neurological Dysfunction in a Mouse Model of Traumatic Brain Injury

Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tis-sue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (M phi) 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/M phi 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/M phi. Intraperitoneal administration of fludarabine, a selective STAT1 inhib-itor, markedly alleviated proinflammatory Mi/M phi responses and brain inflammation burden after TBI. Such phenotype-modulating effects of fludarabine on post-TBI Mi/M phi were reproduced by tamoxifen-induced, selective KO of STAT1 in Mi/M phi (STAT1 mKO). By propelling Mi/M phi away from a detrimental proinflammatory phenotype, STAT1 mKO was sufficient to reduce long-term neuro-logic 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/M phi after TBI. We also showed promising preclinical data sup-porting the use of fludarabine as a novel immunomodulating therapy to TBI.

Automated summary

Traumatic brain injury (TBI) induces inflammation in the brain, resulting in secondary injury and hindered tissue repair. This study investigates the role of transcription factor STAT1 in inflammatory responses after TBI and suggests it as a potential therapeutic target. The inhibition of STAT1 reduces inflammation and improves outcomes in TBI.