The role of CXCL10-CXCR3 axis in the compounding effects of diabetes mellitus in periodontitis - Abstract Poorly controlled diabetes mellitus (DM) exacerbates periodontitis (PD) development and progression. In addition, the management of PD in patients with uncontrolled DM remains a clinical challenge. In fact, PD constitutes the sixth most frequent complication of DM. However, the mechanisms by which DM compounds PD are not fully understood, although a heightened inflammatory response plays a central role. Among the major inflammatory mediators of DM is CXCL10. Interestingly, CXCL10 also plays an important role in PD. CXCL10 expression levels are higher in periodontally diseased tissues and in the serum of patients with PD. Moreover, our laboratory has shown that the CXCL10-CXCR3 axis is fundamental for PD development. We demonstrated that experimentally-induced periodontal bone loss (EPD), in mice, is significantly reduced when the CXCL10 receptor CXCR3, is deleted. Moreover, systemic, and local delivery of a CXCR3 antagonist attenuates EPD, pointing to the targeting of CXCL10 as a potential intervention for PD. Given that DM exacerbates PD, and the key role of CXCL10 as an inflammatory mediator of DM and PD, we hypothesize that CXCL10 is central in mediating the detrimental effects of DM and PD. Thus, targeting the CXCL10-CXCR3 axis should ameliorate the deleterious effects of DM in the periodontium and is a potential therapeutic strategy for the periodontal management of patients with uncontrolled DM. To accomplish our goal, we have two specific aims (SA). SA1: Further elucidate the role of CXCL10 in the periodontium by deleting CXCL10 (SA1a) and by administering CXCL10 systemically (SA1b). SA2: Determine the inhibition of periodontal destruction by a CXCR3 antagonist in mice with DM. In this aim, we will evaluate if local delivery of nanoparticles containing a CXCR3 antagonist, AMG-487, could mitigate the effects of DM in the PD. In brief, DM will be induced in mice, EPD will be developed, and AMG-487 will be delivered locally in slow-releasing nanoparticles. These experiments will provide proof-of- principle evidence for targeting CXCL10-CXCR3 signaling in periodontal inflammation in patients with DM. The long-term goal of our research is to dissect the role of CXCL10 in the exacerbation of PD by DM and to lay the foundation for developing a novel therapeutic approach to assist in the periodontal treatment of patients with uncontrolled diabetes.
