Abstract
Periodontitis is caused by an oral microbial dysbiosis-mediated imbalance of the local immune microenvironment, which is promoted by insulin resistance and obesity. The prevalence and severity of periodontitis is higher in patients with type 2 diabetes than in healthy individuals, possibly because of differences in immune responses. The level of glycemic control also affects the saliva profile, which may further promote periodontal disease in diabetes patients. Therefore, we compared the salivary exosomal miRNA profiles of patients with type 2 diabetes with those of healthy individuals, and we found that exosomal miR-25-3p in saliva is significantly enriched (by approximately 2-fold, p < 0.01) in obese patients with type 2 diabetes. We also identified CD69 mRNA as a miR-25-3p target that regulates both activation of γδ T cells and the inflammatory response. Knockdown of CD69 increased (by approximately 2-fold) interleukin-17A production of γδ T cells in vitro. To evaluate the role of exosomal miRNA on progression of periodontitis, we analyzed regional immune cells in both periodontal tissues and lymph nodes from mice with periodontitis. We found that diet-induced obesity increased the population of infiltrating pro-inflammatory immune cells in the gingiva and regional lymph nodes of these mice. Treatment with miR-25-3p inhibitors prevented the local in vivo inflammatory response in mice with periodontitis and diet-induced obesity. Finally, we showed that suppression of interleukin 17-mediated local inflammation by a miR-25-3p inhibitor alleviated (by approximately 34%) ligature-induced periodontal alveolar bone loss in mice. Taken together, these data suggest that exosomal miR-25-3p in saliva contributes to development and progression of diabetes-associated periodontitis. Discovery of additional miR-25-3p targets may provide critical insights into developing drugs to treat periodontitis by regulating γδ T cell-mediated local inflammation.
Highlights
Periodontitis is a common chronic inflammatory disease that is primarily caused by the host inflammatory response to the bacterial challenge presented by the biofilm
To identify the immune phenotype of obesity-induced insulin resistance leading to local inflammation, we used a periodontitis mouse model that recapitulated the effects of diet-induced obesity and insulin resistance on the severity of disease
We investigated the role of salivary exosomal miRNAs in progression of periodontitis in mice with dietinduced obesity and insulin resistance
Summary
Periodontitis is a common chronic inflammatory disease that is primarily caused by the host inflammatory response to the bacterial challenge presented by the biofilm. The pathogenic mechanism of periodontitis is an oral microbial dysbiosismediated imbalance of the local immune microenvironment, which may develop intermittently into a systemic inflammatory response [1]. Inflammation is a key pathogenic feature of both periodontitis and diabetes, and diabetes patients who poorly control their glycemic response are at greater risk for periodontitis than normoglycemic individuals [2, 3]. Periodontal inflammation can increase the level of glycosylated hemoglobin and (subsequently) cause either prediabetes or overt diabetes [4]. Active periodontal therapy improves glycemic control in patients with type 2 diabetes (T2D) [5]. The precise mechanisms that underpin the links between diabetes and periodontitis are not completely understood
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