Role of JAK inhibition in modulating periodontitis.

Abstract

Periodontitis shares chronification and persistent low-grade inflammation with many chronic diseases, including rheumatoid arthritis, colitis, and Crohn's disease. In all these conditions, there is a gradual impairment of the immune response, increasing susceptibility to infections. Cytokines relevant in inflammatory diseases such as rheumatoid arthritis and periodontitis act through the JAK/STAT signal transduction pathway. Activated JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly STAT proteins, which regulate the transcription of several genes that participate in the inflammatory response. JAK activation therefore appears to be critical in the pathogenesis of inflammatory diseases. Supported by clinical and preclinical evidence of the relevance of this signaling pathway for the progression of arthritis, the use of JAK inhibitors was recently approved for use in humans. Phase II and III clinical trials evaluating the use of inhibitors in the treatment of colitis, Crohn's disease, psoriasis and dermatitis are ongoing. Results have demonstrated significant improvement in the signs and symptoms of these conditions, in addition to a safe pharmacological profile and long-term effectiveness of the inhibitors. In periodontal disease, few studies have evaluated the role of JAK in the pathogenesis process and the results are divergent. Increased inflammatory infiltrate and expression of pro-inflammatory mediators were associated with protein inhibition in an experimental model of periodontitis in mice, suggesting an anti-inflammatory role for JAK. Interestingly, improvement in periodontal clinical parameters was observed in patients with arthritis treated with a JAK inhibitor, indicating its plausible role in modulating periodontitis. Data from our group corroborate the clinical results, demonstrating that JAK inhibition reduces the expression of inflammatory mediators in periodontal ligament cells, blocks osteoclastogenesis in macrophages and induces bone formation in pre-osteoblastic cells. Furthermore, we demonstrated that the selective inhibition of the JAK3 isoform in cells of the periodontal microenvironment modulates the expression of IL-6 and TNF-± more efficiently when compared to the JAK1-3 inhibitor, proposing a greater role of this isoform in periodontitis. Increased inflammatory infiltrate and expression of pro-inflammatory mediators were associated with protein inhibition in an experimental model of periodontitis in mice, suggesting an anti-inflammatory role for JAK. Based on our results and on clinical and preclinical trials indicating a pro-inflammatory role of JAK in inflammatory diseases, the hypothesis of this study is that JAK inhibition may favor tissue repair. This hypothesis will be investigated through the inhibition of different protein isoforms (JAK1-3, JAK3) in a murine model of experimental periodontitis in vivo, and in vitro in tissue turnover cells (periodontal ligament fibroblasts), BMSCs (macrophages and primary osteoblasts) and immune cells (neutrophils). The influence of inhibitor selectivity (JAK1-3 and JAK3) as well as the inhibition strategy (pharmacological inhibitors versus adenoviral vector-borne shRNA inhibition) on the outcomes outlined will be secondarily investigated.