Unraveling non-cranial trauma-induced neuroinflammation: tracing the path of cerebral dysfunction after systemic inflammation remote from various forms of trauma

Severe trauma triggers extensive local and systemic inflammatory responses, leading to secondary end-organ damage. Despite this, the ramifications of post-traumatic immune responses on the brain, particularly after non-cranial injury, have largely been overlooked. In this study, we aimed to examine the effects of non-cranial polytrauma-induced systemic inflammation with or without the addition of blast overpressure on eight distinct brain regions. Adult male rats either received (1) a whole-body blast overpressure exposure [120kPa; BOP], (2) complex extremity trauma [CET] consisting of femoral fracture, soft-tissue crush injury followed three-hours of tourniquet-induced ischemia and immediate hind limb amputation, (3) a full-thickness skin burn [BU] or (4) BOP+CET. Rats (n = 5-7 /timepoint / injury pattern) were euthanized at 6, 24, and 168 hours (h) post-injury. Eight distinct brain regions were dissected and analyzed using RT-qPCR to assess neuroinflammatory-neurodegenerative gene expression changes as compared to naïve age-weight match controls (n =7). Our data indicates a distinct temporal pattern in gene transcripts for several chemokines/cytokines (Csf3, Cxcr2, Il16, Tgfb2), neurosteroids/prostaglandins (Cyp19a1, Ptger2, Ptger3), and neurodegeneration markers (Gfap, Hpca, Ntrk2) following BOP alone, marked by a significant progressive increase (2-15-fold) from 6 to 168 hours post-injury in the amygdala and thalamus. Interestingly, CET triggered an earlier (6 h) and more robust neuroinflammatory response across brain regions compared to BOP, as evidenced by a further 2-120-fold increase in the upregulation of the previously mentioned genes. BOP+CET resulted in the most severe and prolonged neuroinflammatory response. In all injury groups, neuroinflammation increased steadily over the 7-day observation window, while gene expression and clinical measurements of secondary organ damage in lung, liver, and kidney were waning or resolved by day-7. A t-Distributed Stochastic Neighbor Embedding (t-SNE) plot, which is used to visualize complex, multi-dimensional data by grouping similar data points, revealed the striatum’s spatial gene expression pattern was distinct from all other brain regions, which may explain why it is less susceptible to injury. Conversely, the thalamus and hypothalamus showed the greatest relative susceptibility, indicating that non-cranial polytraumatic injury may disrupt sensory relay and homeostasis vital for maintaining neurological health. Strikingly, our findings indicate that non-cranial polytrauma-induced systemic inflammation results in a globally heightened and prolonged neuroinflammatory response that persists beyond seven days, whereas similar injuries in secondary end-organs typically resolve within this timeframe. These findings warrant future studies (genomic, proteomic, metabolomic) on immune responses beyond seven days and longitudinal functional/behavioral testing to assess cognitive, locomotor, and anxiety-related deficits in tandem with gene expression data.