Increased Cortical Interleukin‐1 Receptor Signaling Following Blast‐Induced Traumatic Brain Injury

Abstract

Traumatic Brain Injury (TBI) is a leading cause of disability in the United States resulting in an estimated annual economic cost of over $75 billion. Furthermore, there is a lack of any FDA approved medications aimed at ameliorating the effects of acute injury or the chronic comorbidities of TBI. Those affected are often left with profound chronic neurologic deficits such as major depressive disorder (MDD), anxiety, sleep disturbances, and/or post‐traumatic epilepsy. Neuroinflammation is a hallmark of TBI, although whether neuroinflammatory signaling contributes to the etiology of neuropsychiatric complications following various forms of neurotrauma is not well characterized. We hypothesize that following TBI, interleukin‐1 alpha (IL‐1α) and interleukin‐1 beta (IL‐1β) signaling through functional type 1 interleukin‐1 receptors (IL‐1R1) acts to orchestrate molecular signaling that contributes to the generation of neuropsychiatric sequelae. To test this hypothesis, the current study aimed to characterize alterations in interleukin‐1 (IL‐1) signaling elicited by blast‐induced TBI in murine subjects. Moderate blast‐induced TBI (≈ 20 psi) resulted in an acute increase in righting reflex time (RRT) and a transient decrease in total locomotor activity 3 hrs post‐injury. Rapid increases in il‐1β, il‐1α and tnf‐α mRNA expression occurred in cortical and hippocampal samples ipsilateral to injury in TBI subjects as compared to their sham counterparts, indicating increased CNS production of proinflammatory cytokines. Elevated levels of il‐1r1 mRNA were found in the ipsilateral cortex following injury, however no changes were found in interleukin‐1 receptor associated kinase‐4 (irak‐4) mRNA expression, providing evidence of increased cortical IL‐1R1‐mediated signaling in TBI subjects. Further, TBI resulted in increased mRNA expression and immunoreactivity of the astrocytic marker glial fibrillary acidic protein (GFAP) in the ipsilateral cortex as compared to sham subjects 24 and 72 hrs post‐injury, respectively, indicative of significant reactive astrogliosis. One‐week post‐injury, TBI increased despair‐like behavior as compared to sham treatments as determined by the Porsolt forced swim test (FST). Importantly, no concomitant alterations in general locomotor activity were found in TBI subjects one‐week post‐injury. Future studies will utilize murine models, affording the conditional elimination and restoration of IL‐1R1 in conjunction with blast‐induced TBI to ascertain the cell‐specific contributions of IL‐1R1‐mediated signaling to injury‐induced neuroinflammation and functional outcomes post‐injury. Systematic characterization of IL‐1R1 signaling post‐injury will lead to a better understanding of how neuroinflammatory signaling contributes to the acute and chronic neurologic sequelae of TBI and may lead to viable pharmacotherapeutic targets aimed at ameliorating these deficits.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.