Traumatic brain injury (TBI) is the leading cause of death and disability for people <45 years of age, accounting for nearly 30% of all injury-related fatalities. An estimated 5.3 million Americans are currently living with long-term TBI-related disability. Severe injuries can increase the risk of complications that further compound injury severity. Indeed, TBI patients are considered to be at high risk for infection. Nearly 50% of all TBI patients will develop a secondary infection in the hospital setting. The infection-related mortality rate for TBI patients is ~30%, disproportionately higher than stroke or burn injury, further underscoring the importance of the bidirectional communication between the brain and the immune system. The events that lead to post-TBI immune paralysis are rarely modeled, and as a result, our understanding of the cellular mechanisms underlying the increased vulnerability to infection remains poor. Moreover, the long-term consequences of TBI on systemic immunity are unknown. The dearth of experimental data and lack of long-term patient follow-up studies means that the potential for TBI to permanently alter microglia/macrophage behavior remains an open question. Previously published data from our laboratory has shown that TBI drives progressive neurodegenerative changes due to chronic microglial activation. New preliminary data suggests that TBI induces a persistent immune dysfunction that simulates age-related senescence as evidenced by chronic microglial dystrophy and impaired macrophage responses to secondary immune challenges. At the cellular level, these include deficits in lysosomal function, phagocytosis and respiratory burst activity, as well as elevated cytokine production and oxidative stress. In this proposal we will determine whether TBI causes injury-induced microglia/macrophage senescence, permanent immune dysfunction, and if the targeted removal of senescent cells in TBI mice improves functional outcomes.
Aim 1 will characterize the functional properties and senescent signature of microglia and bone marrow (BM)-derived macrophages isolated from young TBI mice at chronic timepoints compared to sham and aged controls.
Aim 2 will determine whether post-TBI changes in macrophage function are epigenetically driven, and will determine the functional effect that chronically altered BM cells have on CNS behavior using BM chimeras.
Aim 3 will employ the senolytic drug Navitoclax (ABT263) for proof- of-principle of a therapeutic strategy to treat the chronic effects of TBI. The overall goal of this proposal is to identify key hallmarks of TBI-induced immune paralysis, and investigate mechanisms underlying chronic microglia/macrophage dysfunction in TBI. Targeted elimination of senescent immune cells may offer a novel therapeutic approach to restore beneficial properties of the inflammatory response and enhance functional recovery after TBI.

Public Health Relevance

Existing data demonstrate a compelling link between traumatic brain injury (TBI) and immunosuppression in patients leading to greater susceptibility to infections, worsened neurological outcome, and higher mortality. Our understanding of the long-term effects of TBI on innate immune function is woefully limited given the lack of experimental modeling and patient follow-up studies. This proposal will examine the immunoregulatory pathways involved in chronic macrophage dysfunction following TBI and seeks to define new targets for treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Schools of Medicine
United States
Zip Code