JAK inhibition as a modulatory strategy in periodontitis

• Grant number: 22/04466-3
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2022 - June 30, 2024
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Morgana Rodrigues Guimarães Stabili
• Grantee: Morgana Rodrigues Guimarães Stabili
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Fábio Renato Manzolli Leite

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 that can modify the susceptibility and severity of the disease. Furthermore, the concomitant development of other chronic diseases, e.g., arthritis and diabetes, exacerbates the course of periodontitis and impairs post-therapy repair. The use of the periodontitis model has great potential to expand our understanding of the process of chronification and repair of inflammatory lesions.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, and it is, therefore, critical in the pathogenesis of inflammatory diseases. Supported by clinical and preclinical evidence demonstrating the relevance of this signaling pathway for the progression of arthritis and multiple sclerosis, the use of JAK inhibitors has recently been approved for clinical use. 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 disease 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. On the other hand, interestingly, improvement of periodontal clinical parameters was observed in patients with arthritis treated with JAK inhibitor, indicating its plausible role in modulating periodontitis. Preliminary 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 confirmed 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. 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 can prevent the progression of periodontitis and favor tissue repair. This hypothesis will be investigated through the inhibition of different protein isoforms (JAK1-3, JAK3) in murine models 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 will be secondarily investigated. (AU)