Immunometabolic Regulation of MDSCs in Periodontitis

PROJECT SUMMARY/ABSTRACT Periodontitis is a common chronic inflammatory disease affecting over half of the US adult population and characterized by destruction of the supporting structures of the teeth. Although there is a clear relationship between increased obesity and periodontal disease incidence, the mechanisms that underpin the links between these two conditions are not completely understood. Chronic low-grade systemic inflammation in response to obesity, referred to as metainflammation, is a consequence of immune dysregulation that results from the continuous exposure to bacterial lipopolysaccharide and saturated free fatty acids under hyperglycemic conditions. Obesity is known to cause the expansion of immature myeloid cells, termed myeloid-derived suppressor cell (MDSC) populations, which can differentiate into mature osteoclasts, resulting in alveolar bone loss. In this application, it is hypothesized that MDSC expansion and mobilization contribute towards obesity- associated periodontitis through MDSC metabolic reprograming with increased osteoclastic capacity contributing towards alveolar bone loss. The aims outlined in this application will address questions to determine: 1) the mechanisms that govern obesity-directed MDSC subpopulation mobilization and function in the periodontal microenvironment; 2) how obesity or HFD, independent of obesity, contributes toward M-MDSC osteoclastogenic reprogramming potential, and 3) if obesity status contributes towards differences in MDSC subpopulations in human periodontal disease. At the conclusion of these studies, new evidence will be provided related to the cellular mechanisms engaged during diet-induced obesity that contribute towards periodontal disease susceptibility and progression through MDSC populations in mice and humans.