Peripheral immune cell dysregulation following diffuse traumatic brain injury in pigs.

Abstract

Traumatic brain injury (TBI) is a global health problem affecting millions of individuals annually, potentially resulting in persistent neuropathology, chronic neurological deficits, and death. However, TBI not only affects neural tissue, but also affects the peripheral immune system's homeostasis and physiology. TBI disrupts the balanced signaling between the brain and the peripheral organs, resulting in immunodysregulation and increasing infection susceptibility. Indeed, secondary infections following TBI worsen neurological outcomes and are a major source of mortality and morbidity. Despite the compelling link between the damaged brain and peripheral immune functionality, little is known about how injury severity affects the peripheral immune system in closed-head diffuse TBI, the most common clinical presentation including all concussions. Therefore, we characterized peripheral blood mononuclear cells (PBMCs) and plasma changes over time and across injury severity using an established large-animal TBI model of closed-head, non-impact diffuse rotational acceleration in pigs. Across all timepoints and injury levels, we did not detect any changes to plasma cytokine concentrations. However, changes to the PBMCs were detectable and much more robust. We observed the concentration and physiology of circulating PBMCs changed in an injury severity-dependent manner, with most cellular changes occurring within the first 10 days following a high rotational velocity injury. Here, we report changes in the concentrations of myeloid and T cells, changes in PBMC composition, and changes in phagocytic clearance over time. Together, these data suggest that following a diffuse brain injury in a clinically relevant large-animal TBI model, the immune system exhibits perturbations that are detectable into the subacute timeframe. These findings invite future investigations into therapeutic interventions targeting peripheral immunity and the potential for peripheral blood cellular characterization as a diagnostic tool.