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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 KO 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 neurologic 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/MU after TBI. We also showed promising preclinical data supporting the use of fludarabine as a novel immunomodulating therapy to TBI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is commonly followed by long-term cognitive deficits that severely impact the quality of life in survivors. Recent studies suggest that microglial/macrophage (Mi/MΦ) polarization could have multidimensional impacts on post-TBI neurological outcomes. Here, we report that repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles for 4 weeks after controlled cortical impact improved hippocampus-dependent spatial and non-spatial cognitive functions in adult C57BL6 mice, as assessed by a battery of neurobehavioral tests for up to 5 weeks after TBI. IL-4-elicited enhancement of cognitive functions was associated with improvements in the integrity of the hippocampus at the functional (e.g., long-term potentiation) and structural levels (CA3 neuronal loss, diffusion tensor imaging of white matter tracts, etc.). Mechanistically, IL-4 increased the expression of PPARγ and arginase-1 within Mi/MΦ, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi/MΦ-specific PPARγ knockout (mKO) mice, indicating an obligatory role for PPARγ in IL-4-induced Mi/MΦ polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPARγ mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPARγ-dependent beneficial Mi/MΦ responses, and improves hippocampal function after TBI. [ABSTRACT FROM AUTHOR]

The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.