ROR Inverse Agonist Suppresses Insulitis and Prevents Hyperglycemia in a Mouse Model of Type 1 Diabetes
Year: 2015
Type: article
Abstract: Hyperglycemia associated with type 1 diabetes is a consequence of immune-mediated destruction of insulin producing pancreatic β-cells. Although it is apparent that both CD8(+) T cells and TH1 cells are key contributors to type 1 diabetes, the function of TH17 cells in disease onset and progression remains unclear. The nuclear receptors retinoic acid receptor-related orphan receptors-α and γt (RORα and RORγt) play critical roles in the development of TH17 cells and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity. To investigate the roles and therapeutic potential for targeting the RORs in type 1 diabetes, we administered SR1001, a selective RORα/γ inverse agonist, to nonobese diabetic mice. SR1001 significantly reduced diabetes incidence and insulitis in the treated mice. Furthermore, SR1001 reduced proinflammatory cytokine expression, particularly TH17-mediated cytokines, reduced autoantibody production, and increased the frequency of CD4(+)Foxp3(+) T regulatory cells. These data suggest that TH17 cells may have a pathological role in the development of type 1 diabetes, and use of ROR-specific synthetic ligands targeting this cell type may prove utility as a novel treatment for type 1 diabetes.
Source: Endocrinology
DOI: 10.1210/en.2014-1677
Authors: Laura A. Solt, Subhashis Banerjee, Sean Campbell, Theodore M. Kamenecka, Thomas P. Burris
Institutions: Scripps Research Institute, Saint Louis University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2116511006