The effects of repeat mild traumatic brain injuries on choroid plexus endothelial cells in-vitro

Abstract

Chronic Traumatic Encephalitis (CTE) is a degenerative brain disorder seen in college and professional football players, and those that play other contact sports like hockey and soccer. It is characterized by a dementia-like phenotype and declination in memory, executive dysfunction, and mood and is associated with repetitive head trauma, as seen in those contact sports. Even with rule changes to protect the players, it is predicted that, on average, college football players experience 1,400-1,500 head impact exposures per year, or roughly 14 per game (Crisco et al., 2010). This is significant because existing literature provides evidence that it is the accumulation of repetitive head trauma, even mild, that eventually leads to lasting and irreparable damage seen in CTE. This study sought to characterize cytokine signaling in repeat mild traumatic brain injuries (rTBI) in choroid plexus endothelial cells (CPECs), the endothelial barrier of the blood-CSF barrier (BCSFB). We hypothesized that regulatory and pro-inflammatory cytokines and chemokines play a role in exacerbating post-rTBI symptomology even days after initial injury. Identifying key cytokines and their respective timepoints post-injury is important to allow us to better treat TBIs, while also preventing subsequent damage that might progress to CTE. To study this hypothesis, primary human CPECs were subjected to a 12% repetitive mechanical elongation strain using the FlexCell Tension system to mimic mild axonal stretching injury. The elongation mechanical strain was repeated 14 times over a 1-hour period, which is roughly the average number of impacts experienced by players during a one-hour college football game. We collected supernatant over 24-, 48-, 72-, and 96-hours post-injury and examined 36 different cytokines using RND microarrays following manufacturer’s instructions. Controls included cells subjected to no mechanical strain and cells that only received one total mechanical strain. Several notable cytokines and chemokines were altered during this period, including RANTES (CCL5), CXCL12, and macrophage migration inhibitory factor (MIF). RANTES is highly correlated with Alzheimer’s disease, a neurodegenerative disease and CTE relative, and CXCL12 and MIF are highly correlated with inflammatory processes. Many cytokine changes were more pronounced in the period between 24- and 48-hours after injury. However, there were lasting changes compared to the controls up to 96-hours later. These findings can be used to begin to understand the complexity of human CPEC cytokine signaling at the BCSFB when these cells react to the strain forces of repeat mild TBIs like those seen in college football players. This also gives us further insight into the lasting effects of rTBIs and the possible relation to CTE. With these results in mind, we plan to continue to monitor cytokines and chemokines up to two weeks post injury to determine if, and when, cytokine values return to baseline values post-injury. This project was funded by a Senior Research Grant from the Indiana Academy of Science and from a Faculty Research Development Grant from Marian University College of Osteopathic Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.