A Levee to the Flood: Pre-injury Neuroinflammation and Immune Stress Influence Traumatic Brain Injury Outcome

Abstract

Increasing evidence demonstrates that aging influences the brain's response to traumatic brain injury (TBI), setting the stage for neurodegenerative pathology like Alzheimer's disease (AD). This topic is often dominated by discussions of post-injury aging and inflammation, which can diminish the consideration of those same factors before TBI. In fact, pre-TBI aging and inflammation may be just as critical in mediating outcomes. For example, elderly individuals suffer from the highest rates of TBI of all severities. Additionally, pre-injury immune challenges or stressors may alter pathology and outcome independent of age. The inflammatory response to TBI is malleable and influenced by previous, coincident, and subsequent immune insults. Therefore, pre-existing conditions that elicit or include an inflammatory response could substantially influence the brain's ability to respond to traumatic injury and ultimately affect chronic outcome. The purpose of this review is to detail how age-related cellular and molecular changes, as well as genetic risk variants for AD affect the neuroinflammatory response to TBI. First, we will review the sources and pathology of neuroinflammation following TBI. Then, we will highlight the significance of age-related, endogenous sources of inflammation, including changes in cytokine expression, reactive oxygen species processing, and mitochondrial function. Heightened focus is placed on the mitochondria as an integral link between inflammation and various genetic risk factors for AD. Together, this review will compile current clinical and experimental research to highlight how pre-existing inflammatory changes associated with infection and stress, aging, and genetic risk factors can alter response to TBI.

Divergent Spatial Learning, Enhanced Neuronal Transcription, and Blood–Brain Barrier Disruption Develop During Recovery from Post-Injury Sleep Fragmentation

“…Genes associated with cellular metabolism and responses to oxidative stress ( Etv5 , Nmnat2 , and Atp2a2 ) were also increased with TBI SF-R, indicating mitochondrial dysfunction, which is evident with TBI and stress and contributes to chronic neuroinflammation. 54 …”

Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury

“…Persistent or intense stress is harmful and can exacerbate neurological dysfunction. However, the mechanisms through which stress affects post-injury recovery depend on the timing and type of stressor, and some studies suggest that stress can even improve outcomes after TBI (reviewed by Houle and Kokiko-Cochran, 2022 ; Zheng et al, 2022 ).…”

Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury

“…Thus, pre-conditioning is an important consideration when discussing pre-injury immune activators. There are many other sources of pre-injury immune stress that have been reviewed elsewhere ( Houle and Kokiko-Cochran, 2022 ). Taken together, these data demonstrate that the synergistic effects of TBI and stress can greatly impact recovery.…”