TBI is a major cause of disability and a significant burden to health care costs in the US. TBI management lacks effective pharmacological treatment. Neuroinflammation is a component of secondary injury that can worsen brain injury, and it progresses over time, thus allowing opportunities to pharmacologically intervene. The goal of this project is to better understand a novel microglia subset in TBI, and determine whether it is a cellular mechanism driving pathology in TBI. We hope that knowledge of microglia heterogeneity will lead to more effective and precise therapeutic approaches or help identify biomarkers for TBI. Our vision is to target inflammatory microglia subsets to block harmful responses, while allowing neuroprotective microglia to promote wound repair. We used the unbiased approach of single-cell RNA sequencing to identify several microglia subsets induced by acute, sub-acute, and chronic TBI in mice. The gene expression profile Irf7hi microglia significantly express RNA of several interferon-stimulated genes (ISGs) indicating that they are responding to type I IFNs, such as IFN?. It has been shown the type I IFN pathway is harmful in TBI. However, the mechanisms, cells, or subsets of cells mediating this pathway have not been elucidated. We hypothesize that the Irf7hi microglia subset worsens TBI, and that dampening of IFNAR1 in microglia by genetic and pharmacological targeting will reduce the activation of this microglia subset and improve TBI. The type I IFN response is relevant to civilian TBI as IFN? is significantly upregulated in the plasma of human patients within 6 hours post-TBI. We will test whether the mechanism of the type I IFN-mediated pathway mediating detrimental effects in mice is due to Irf7hi microglia. In our first aim, we propose to investigate the temporal dynamics and spatial localization of Irf7hi microglia to determine its persistence and progression during acute, sub-acute, and chronic TBI by histology and single-cell RNA seq. Sex differences in the response to TBI will be examined by high-throughput multiplexing approaches. In our second aim, we will test the impact of conditionally targeting IFNAR1 and possibly STING in microglia. Inflammation, histopathology, and behavior post-TBI will be evaluated.
Our third aim will employ a new approach of therapy for TBI by using antisense oligonucleotides (ASOs) designed to knock down IFNAR1 or IRF7 gene expression. We will test the capacity of these ASOs to improve TBI in a preclinical study. Studies of microglia subsets will be reciprocally informative across neuroinflammatory diseases. This proposal is mechanistic, and translationally relevant to the clinic. Elucidation of critical innate immune cell subsets during neuroinflammation will advance TBI and neuroscience research.

Public Health Relevance

Traumatic brain injury (TBI) is a widespread and devastating problem that affects all ages, but with particular high incidence for soldiers in the military. Neuroinflammation is a significant component of secondary brain injury that can worsen brain damage. Current results from strategies targeting innate immunity to treat acute brain injury are encouraging. We use an experimental mouse model of TBI to apply elegant approaches to study neuroinflammation. For this proposal, we seek to better understand changes in the immune response to TBI over time, including during chronic TBI. In collaboration with pharmaceutical companies, we test the efficacies of therapeutic approaches that have not been tested in TBI before to alter inflammation and improve functional behavior outcomes in preclinical studies. In particular, we will determine the cellular mechanisms driving a potent innate immune pathway propagated by type I interferons in TBI, and test targeting these cells/pathway to treat TBI in preclinical studies. Our goal is to improve functional recovery for veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Veterans Affairs Medical Center San Francisco
San Francisco
United States
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