Systemic inflammation induced from polysystem trauma is a critical driver of temporal and spatially resolved gene expression in key regional compartments of the injured brain

Blast exposure can cause devastating life-threatening polysystem trauma. Despite considerable efforts, the role of the systemic inflammation following major trauma on secondary brain injury is largely unknown. In this study, we aimed to identify and delineate altered neuroinflammatory signaling responses in regional compartments of the brain following various traumatic injuries. Adult male rats (400-500 g) either received a (1) head-on whole-body blast overpressure exposure only (120 kPa; BOP), (2) complex extremity trauma (CET) involving closed femoral fracture and soft-tissue crush injury, 3 hours (h) of prolonged tourniquet-induced limb ischemia and limb amputation through the zone of injury, or (3) BOP+CET. At 6, 24, and 168 h post-injury cohorts of rats (n=7 timepoint/model) were euthanized and eight anatomic regions of the brain were dissected and profiled for neuroinflammatory-neurodegeneration gene expression signatures using a custom low-density RT-qPCR microarray. We compared the molecular heterogeneity of gene profiles of the brain in the steady state of naïve animals with trauma-induced changes over time. Differential gene expression (DEG) analysis indicated similar expression patterns of genes involved in neurotransmission and transcription functions across all regions of the naïve brain and known targets involved in perpetuating inflammation to be extremely low or undetectable. Gene expression associated with neuroinflammation and neuropathology were robustly increased acutely after injury where the magnitude of the response across structural brain regions correlated with injury severity (BOP+CET>CET>BOP). We identified a time dependent injury-associated change following BOP, wherein few DEGs were detected at 6 h post-injury, yet excessive significant pathological changes in neuroinflammatory cascades were detected 168 h post-injury occurring primarily in the hippocampus, amygdala, and thalamus. In contrast, remote extremity trauma (CET) in the absence of direct brain injury resulted in a much earlier diverse, and aberrant neuroinflammatory response across most brain regions, a majority of which remained elevated at 168 h. BOP+CET resulted in a global heightened and prolonged neuroinflammatory response comprising expression of additional functional regulatory networks genes linked to immune cells, immune mediators and immune signaling pathways. These findings provide a foundation for discerning the pathophysiological consequences of acute extremity injury-induced systemic inflammation on promoting remote brain neuroinflammation, which ultimately may contribute to pathological dysfunction and cognitive impairment.