DELINEATING IMMUNE-MEDIATED MECHANISMS OF DISEASES AFTER TRAUMATIC INJURY
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Date
2021-01-01
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Department
Chemical, Biochemical & Environmental Engineering
Program
Engineering, Chemical and Biochemical
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Distribution Rights granted to UMBC by the author.
Access limited to the UMBC community. Item may possibly be obtained via Interlibrary Loan thorugh a local library, pending author/copyright holder's permission.
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Abstract
Traumatic brain injury (TBI) is one of the most common causes of disability and death around the world. TBI patients often suffer long-term neurological dysfunction and disabilities and have a higher risk of developing chronic neurodegenerative diseases. Elderly TBI patients have a higher mortality rate and suffer worse outcomes. Persistent and progressive neuroinflammation after TBI is one of the major drivers of chronic neurodegeneration. Microglia are brain-resident immune cell that activates after TBI to protect the brain from injury. However, uncontrolled and long-lasting microglial activation contributes to neurodegeneration. Several drug candidates have entered clinical trials for TBI treatment. However, no drugs have proven successful in improving neurological function outcomes. The complexity of cellular responses to injury and the short therapeutic window of drug intervention makes developing therapies particularly challenging. Therefore, elucidating the long-lasting immune-mediated responses after TBI may identify novel targets for therapeutic intervention with a wider therapeutic window.In this dissertations, I focused on identifying the immune-mediated mechanisms after TBI in controlled cortical impaction (CCI), a well-characterized mouse experimental TBI model. The transcriptional signatures in the hippocampus showed a robust correlation with neurological functional impairments. Based on transcriptional signatures, microglia-mediated neuroinflammation is a potential therapeutic target during the chronic time frame. To investigate the role of microglia in chronic neuroinflammation and neurodegeneration associated with functional impairments, microglia were depleted starting at four weeks after TBI using a small molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R), remained on treatment for one week, and microglia were allowed to repopulate after cessation of treatment. Transient depletion and repopulation eliminated the destructive neurotoxic microglial phenotype that contributes to neurodegeneration, resulting in improved functional outcomes. The findings further proved that the therapeutic window targeting chronic neuroinflammation may be prolonged from a few hours to a few weeks after injury. TBI-associated inflammation is exaggerated in elderly patients. In this dissertations, a unique state of microglia was identified in the aged brain exhibiting a pro-inflammatory and senescent phenotype, with altered lipid signaling, endocytosis, and metabolism. CSF1R-mediated microglia depletion and repopulation eliminated the pro-inflammatory and senescent microglia. Furthermore, inflammation after injury is exacerbated in the old brain, and these effects were attenuated by transient depletion of microglia, suggesting that age-associated neuroinflammation exacerbation after TBI may be treatable. In summary, these findings suggest that drug intervention with a wider therapeutic window targeting microglia-mediated chronic neuroinflammation after TBI is possible in elderly patients.