Divergent age-dependent peripheral innate immune response following TBI

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ABSTRACT Neuroinflammation has emerged as a critical component of secondary injury following brain trauma. Recent pre- clinical studies have shed light on the neurotoxic effects of peripheral-derived monocyte/macrophages (PDM). Our preliminary findings suggest this response may be dampened in the presence of juvenile-derived murine PDMs, however the cause of this neuroprotective response remains unknown. The research objective of this application is to characterize the cellular and molecular mechanism(s) underlying the divergent, age-dependent PDM response and their role in mediating neurovascular dysfunction following TBI. Our proposal builds upon extensive preliminary and published data demonstrating a distinct age-at-injury response following TBI. Juvenile- derived PDMs display reduced pro-inflammatory phenotype, and adult PDM depletion and replacement with those from juvenile mice confer neuroprotection. Moreover, we discovered that PDM-specific Tie2/EphA4 receptor crosstalk regulates their pro-inflammatory state across the age spectrum. We hypothesize that age- related differences in the PDM response underlie divergent outcomes 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 omics assessment of the relevance and mechanism(s) of PDM age on injury outcomes. We will also provide a framework for retooling the neuroinflammatory response to accelerate pro-recovery and dampen pro-inflammatory processes after TBI.