Treatment with synthetic glucocorticoids (GC) has been the frontline approach to treat inflammatory diseases. In the context of multiple sclerosis (MS), an autoimmune inflammatory disorder in the central nervous system mediated by myelin antigen reactive CD4 T cells, high dose steroid therapy (e.g., intravenous methylprednisolone) is effective in downregulating acute relapses and in hastening the recovery from the relapses. Despite the broad usage of GCs, our understanding the underlying mechanism is disappointingly limited. One potential drawback behind GC therapy is that not all patients are responsive to the treatment and they often acquire the status of non-responsiveness, GC resistance. Increasing the doses raises significant health concerns due to wide-ranging adverse side-effects. Therefore, it is imperative to define the precise mechanisms by which GC modulates inflammatory responses. GC exerts its immunotherapeutic actions by binding its cytosolic receptor, GC receptor (GR, encoded by the Nr3c1 gene), which upon ligand binding undergoes conformational changes, translocates into the nucleus, and acts as transcription repressors/activators. It was previously reported that systemic dexamethasone (Dex) administration reduces the severity of experimental autoimmune encephalomyelitis (EAE), an animal model for MS and that T cells are the primary targets of therapeutic actions of Dex, because T cell-specific GR-/- (Lck-Cre Nr3c1-floxed) animals fail to respond to the Dex treatment, while GR deletion on myeloid compartments (LysM-Cre Nr3c1-floxed animals) does not affect Dex-induced treatment of EAE. Foxp3+ regulatory T cells (Treg) are a CD4 T cell subset critically involved in inflammation and tolerance. Lack of Tregs results in systemic autoimmune inflammation. Multiple mechanisms have been proposed to account for regulatory functions of Tregs in vivo, and this is an area of active investigation because the mechanisms appear to be tissue- and disease-specific. One proposed mechanism of GC treatment of inflammation involves its action on Tregs. However, the precise mode of action remains poorly understood. The overarching goal of this application is to investigate the role of Tregs during GC-treatment of autoimmune inflammation, EAE. We made an unexpected compelling observation that Dex-mediated therapeutic effect is completely abolished when Tregs are absent at the time of Dex administration. Since Dex-responsive conventional effector T cells remain intact in this setting, these results strongly suggest that Foxp3+ Tregs may play an important role in mediating therapeutic functions of Dex. In this application, we will test the cellular and molecular mechanisms by which GCs mediate immunotherapeutic actions via Foxp3+ Tregs. Uncovering the interplay between GC and Tregs will have significant impact on developing novel therapies targeting GC receptor in immunoregulatory Tregs.
|Effective start/end date||9/1/20 → 3/31/22|
- National Multiple Sclerosis Society (Grant #: RG-2011-37157)