Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide. Over 1.7 million Americans suffer a TBI annually and up to 2% of the population currently lives with the long-term neurological consequences of a previous TBI, placing a $76.5 billion annual economic burden on society. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized TBI patients die from injuries that are secondary to the initial trauma. Cerebral edema is a life-threatening neurological complication that promotes elevated ICP and leads to clinical deterioration in the hours and days after a TBI. Further, Inflammation, which contributes toward both CNS injury and repair, involves both immediate non-specific innate immunity and long lasting specific adaptive immunity. Unfortunately, neurosurgical approaches to control elevated ICP are limited and efficacious medical therapies to control cerebral edema and inflammation are lacking, presenting a critical barrier to improving patient prognoses after TBI. Ours is a timely and innovative proposal that will find the link between enhancement of endogenous protection through Transient Receptor Potential Vanilloid-1 (TRPV1) and activation of immune cells like macrophages and T cells. The objective of this proposal is to test the overarching hypothesis that activation of TRPV1 attenuates the neurovascular injury after TBI by polarizing infiltrating immune cells into anti-inflammatory phenotypes. Our long-term goal is to define the functional roles for TRPV1 after TBI, which will establish a mechanistic framework to advance the development of immuno-modulatory therapeutics to enhance patient outcomes. To test our hypothesis, we propose the following aims: Specific Aim 1: will test the hypothesis that activation of myeloid TRPV1 promotes neurovascular protection after TBI. Proposed studies will utilize pharmacological, genetic and bone marrow chimera approaches to demonstrate a protective role for TRPV1 activation after TBI. Specific Aim 2: will test the hypothesis that myeloid TRPV1 is required for regulation of T-cells and subsequent chronic recovery after TBI. Proposed studies will utilize myeloid specific TRPV1 knock-in mice to will functionally implicate TRPV1 in T-cell activation and injury resolution after TBI. Expected outcomes include the identification of TRPV1 as a therapeutic target to modulate T cell polarization and injury resolution after TBI. Our proposed studies have far-reaching translational implications, as demonstration of a key role for TRPV1 in TH1/TH17 cells regulation in injury resolution. Chronic immune activation will provide a biomarker to predict recovery in brain injury. Additionally, the results from this study will pave the way for future intensive studies with TRPV1 in co-morbid conditions like hypertension, diabetes etc.