Traumatic brain injury (TBI) affects an estimated 1.5 million people each year and contributes to one third of injury-related deaths. It is well known that the initial injury is exacerbated by a robust and poorly controlled inflammatory response, which contributes to secondary cell death in areas of the brain distant to the initial trauma. The innate immune response to tissue injury is mediated, in part, by the inflammasome, a multi- protein complex that senses endogenous danger signals and is responsible for caspase-1 activation and the production of inflammatory cytokines. The AIM2 (absent in melanoma 2) inflammasome is the most recently identified, and least understood, inflammasome complex. The AIM2 inflammasome is activated by dsDNA and has been characterized in macrophages, predominantly in the context of viral infection. However, the AIM2 inflammasome also responds to self-DNA and induces pyroptosis, a recently-characterized, inflammatory cell death program. My central hypothesis is that AIM2 forms an inflammasome in neurons, is activated by endogenous dsDNA released from necrotic cells following TBI, and contributes to caspase-1 activation, inflammatory cytokine production, pyroptotic cell death, and injury pathology. The objectives of this application are to: (1) identify the structural components and protein associations of the AIM2 inflammasome in primary neurons and neurons activated by dsDNA; (2) determine the role of the AIM2 inflammasome in pyroptotic neuronal death, and (3) determine the extent to which inhibition of the AIM2 inflammasome, after a rat model of TBI, reduces inflammation and leads to improved histopathological and behavioral outcomes. The proposed studies will increase our understanding of secondary neuronal death and the innate immune response following TBI, and aid in the identification of a novel therapeutic target to limit the chronic, progressive loss of neurons following brain injury. PUBLIC HEALTH RELEVANCE: Project Narrative-Relevance Approximately 5.3 million Americans are living today with a permanent disability related to a traumatic brain injury (TBI), and we have no therapies to improve the long-term outcomes of TBI patients. These studies will provide a greater understanding of inflammation and cell death after TBI and aid in the development of treatments so that we may reduce the social and economical burdens of this devastating condition.