Novel mechanisms suppressing the pro-resolving phenotype of peripheral innate immunity following traumatic brain injury

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ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury and disease progression following brain trauma. Recent pre-clinical studies have shed light on the neurotoxic effects of peripheral innate immunity. Our preliminary findings suggest this overzealous response may be mediated by EphA4/mTOR signaling which negatively regulates the anti-inflammatory state of peripheral-derived monocyte/macrophages (PDMs). The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying innate immunity and PDM polarization status in the regulation of tissue damage and functional recovery following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct protective and reduced pro-inflammatory response in the absence of peripheral EphA4 using chimeric mice following controlled cortical impact (CCI) injury. Interestingly, PDMs-derived from EphA4null mice directly confer neuroprotection and blood brain-barrier preservation in a model of monocyte depletion and replacement. Moreover, we discovered that PDM-specific EphA4 suppresses phosphorylation of key proteins involved in the mTOR pathway, a novel mediator of the pro-resolving state of PDMs. We hypothesize that EphA4 mediates the pro-inflammatory innate immune response by suppressing mTOR signaling, which induces PDM infiltration, polarization and phenotypic behaviors that drive neurovascular dysfunction following TBI. We will employ cell-specific depletions, and PDM replacement as well as novel transgenic murine models. These approaches will include rigorous behavioral, histological and innovative low-input genome-wide epigenomic and transcriptomic assessment of the relevance and mechanism(s) of PDM behaviors. We will also provide a framework for retooling the neuroinflammatory response to accelerate recovery and dampen pro-inflammatory processes after TBI.