NOX2 drives microglia-dependent neurodegeneration after traumatic brain injury

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Project Summary: Traumatic brain injury (TBI) triggers delayed molecular secondary injury cascades, including chronic neuroinflammation, that contribute to progressive tissue loss and neurological impairments, including cognitive deficits. Chronic neuroinflammation with sustained microglial activation occurs following severe TBI and is believed to contribute to subsequent neurodegeneration and neurological impairments. Thus, targeting microglial activation may offer novel therapeutic targets for TBI patients. Our previous studies have probed the development of dysfunctional microglia after TBI and shown that: 1) pro-inflammatory microglia are chronically activated up to one year following experimental TBI, contributing to neurodegeneration and cognitive decline; 2) NADPH oxidase (NOX2) plays a critical role for chronic microglial-mediated neurotoxicity; 3) temporary depletion of brain microglia using a CSF1R inhibitor (PLX5622) causes microglial reprograming and phenotypic shift from a chronic pro-inflammatory profile to more restorative phenotypes that express reduced inflammatory markers, including NOX2 , and attenuate long-term motor and cognitive deficits. In the present proposal, we aim to utilize the groundbreaking single-cell RNA-seq analyses to investigate the unique microglial subsets present following specific targeted deletion of NOX2. Furthermore, we will investigate the transcriptional signatures of the microglial subsets that modulate neurorestorative properties in the chronically injured brain. Importantly, this proposal will investigate the role of NOX2 in non-microglia macrophage-like cells, including border-associated macrophages (BAMs) and circulating monocytes, in mediating neuroinflammatory responses and neurological decline, following TBI. Specific aims include: 1) To elucidate the mechanisms of repopulation-induced microglial reprograming associated with attenuated pro-inflammatory, neurotoxic phenotypes after TBI; 2) To determine the role of microglial NOX2 in neuroinflammation/neurodegeneration after TBI; 3) To address the role of BAM NOX2 in in neuroinflammation/neurodegeneration after TBI; and 4) To evaluate the role of circulating monocytes NOX2 in neuroinflammation/neurodegeneration after TBI. Understanding the molecular mechanisms that drive microglia and non-microglia macrophage-like cells to polarize towards a neurorestorative state will be crucial to unlock the endogenous potential of microglia/macrophages to promote repair during the chronic phase of recovery after TBI.