Roles for lymphocyte RANKL in periodontal complications of type 2 diabetes

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Periodontitis fuels the inflammation of obesity-associated type 2 diabetes (T2D), associates with poor glycemic control, and increases T2D morbidity. New strategies are critically needed to counter sources of periodontal infection and the resulting inflammation, both of which are refractory to standard treatments in people with T2D. However, mechanisms underlying the relationship between periodontitis and T2D remain poorly understood, impeding clinical progress. One unifying link between periodontitis and T2D is altered B cell function, and recent collaborative work between Drs. Barbara Nikolajczyk and Thomas Van Dyke showed that T2D-associated changes in B cells promote periodontitis. Our work further indicates that T cells cannot drive chronic periodontitis in T2D hosts in the absence of B cells, despite evidence that T cells promote periodontitis in lean hosts. Taken together, these findings support a model in which B cells support T2D-potentiated periodontitis, while T cells dominate periodontitis in leans. Both B cells and T cells are major sources of receptor activator of nuclear factor kappa-B ligand (RANKL), a key driver of osteoclastogenesis and periodontal bone loss. Obesity/T2D increases hematopoietic cell production of RANKL, most likely through increasing concentrations of a number of cytokines (TNFα, IL-1β and IL-6) known to drive RANKL production. These data, together with our demonstration that B cells are required for T2D-potentiated osteoclastogenesis and periodontitis, support our central hypothesis: T2D cytokines specifically up regulate B cell RANKL function, which uniquely potentiates periodontal complications of T2D. Definitive analyses are needed to fill the critical gaps in knowledge of how obesity-associated T2D impacts lymphocyte RANKL induction and function, and whether cellular sources of osteoclastogenic RANKL differ in T2D compared to lean hosts. We will use loss- and gain-of-function approaches in a standard mouse model of T2D, coupled with a standard model of chronic periodontitis, to study development of T2D-potentiated periodontal disease. We will complement the disease etiology work in mice with analysis of gingiva from people with T2D to query mechanistic underpinnings of chronic periodontitis. This strategy will identify drivers of both early and chronic phases of T2D-potentiated periodontitis to meet our long-term objective: to identify key factors that promote periodontitis in T2D compared to non-T2D subjects, and thereby pinpoint drug targets for future studies.