Role of Irg-1/itaconate in modulating secondary brain damage after traumatic brain injury in mice

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Project Summary: The development of a novel therapeutic strategy to effectively target multiple pathological mechanisms of secondary brain damage after traumatic brain injury (TBI) is a top clinical priority. The metabolic reprogramming of neurovascular inflammatory cells after TBI may contribute to the cellular oxidative/neuroinflammatory stresses and play critical roles in the early triggering and acceleration of secondary brain injury cascades. However, the detailed knowledge remains largely unknown. Recent experimental discoveries demonstrate that itaconate, one of the most abundant tricarboxylic acids (TCA) cycle intermediates, produced by an enzyme called immune-responsive gene 1 protein (Irg-1), may function as a signaling transducer in modulating the metabolic reprogramming. Our central hypothesis is that the Irg- 1/itaconate modulates the metabolic reprogramming and thus controls neurovascular inflammatory signaling pathways of the microglia and the cerebrovascular endothelium by preserving mitochondria oxidative phosphorylation (OXPHOS), suppressing hyperglycolysis/NFκB activation, and activating nuclear factor E2- related factor 2 (Nrf2), which results in the inhibition of microglial activation-associated neuroinflammation, and blood-brain barrier (BBB) integrity disruption; these actions interactively prevent the secondary brain damage and ultimately improve the long-term neurological outcome of TBI. Our preliminary data are highly supportive of our proposed hypotheses and experimental approaches. In this project, we will pursue three integrated aims using bioenergetics/metabolomics and transcriptomics, functional energy metabolic assay of brain slices and isolated cells, and in combination with cell-specific transgenic and pharmacological, molecular pathology, and neurological outcome assessments. In Aim 1, we will investigate the role of microglial Irg-1/itaconate in the modulation of microglial pro-inflammatory activation after TBI. In Aim 2, we will investigate the role of cerebrovascular endothelial Irg-1/itaconate in the modulation of BBB integrity after TBI. In Aim 3, we will investigate the role of itaconate supplementation in long-term neurological outcomes after TBI in mice. The proposed studies will provide detailed insights into the dynamic bioenergetics/metabolic reprogramming of inflammatory microglia and cerebral endothelium, elucidate the role of Irg-1/itaconate in modulating the metabolic reprogramming, and associated neurovascular inflammatory mechanisms after TBI.