Modulation of TGFb-IRF8 and APOE Axis to Restore Homeostatic Microglia and Ameliorate EAE
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease that targets the central nervous system, promoting symptoms that range from fatigue to motor impairment, severely decreasing patients quality of life. Despite advances in our understanding of MS pathophysiology, there are few treatments for the progressive forms of MS. Although the mechanisms that lead to the progression of the disease are unknown, the contribution of glial cells, especially microglial cells, the central innate immunity, may play a major role in this process. It has been postulated that the beneficial or destructive nature of microglial responses are determined by a well-controlled dialogue between the innate and the adaptive immune players, which includes microglia, monocytes, and lymphocytes. However, how this dialogue participates in MS is still unclear. One of the major obstacles to studying microglial biology in disease is the inability to distinguish their contribution to pathological processes. Recently, our group has identified unique homeostatic (M0) and neurodegenerative (MGnD) microglia phenotypes regulated reciprocally by two intrinsic factors, TGF-beta and APOE signaling in multiple neurodegenerative conditions including EAE and MS, and we have developed novel tools to investigate their biology. However, the role of these two major microglial phenotypes and their interaction with immune infiltrates and contribution to disease progression is unknown. This project has as FY21 MSRP Early Investigator Research Award Focus Area the Central Nervous System Regenerative Potential in Demyelinating Conditions. The purpose of my project is restoring microglial regulatory functions to suppress neuroinflammation during disease progression in MS. Our preliminary data showed that inactivation of TGF-beta signaling in microglia downregulates IRF8 expression, a molecule essential for the maintenance and maturation of homeostatic microglia. Conversely, deletion of Apoe restored IRF8 expression and delayed disease onset in an animal model. Importantly, variations in the IRF8 gene are associated with development of secondary progressive MS (SPMS). To assess how the neurodegenerative microglial cells modulate MS demyelination, I will utilize an animal model of multiple sclerosis disease, the experimental autoimmune encephalomyelitis (EAE) crossed to the new transgenic mice models, recently developed in our laboratory, to specifically target and modulate a neurodegenerative microglia subset to restore their homeostatic phenotype and physiological functions. Successful completion of this research proposal will allow us to understand both the beneficial and detrimental functions of microglia during EAE, which will provide new insights into the immunopathogenesis of MS, and potential new neuroprotective and therapeutic strategies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210945
Entities
People
- Wesley Nogueira Brandao
Organizations
- United States Army