The role of CXCL10-CXCR3 axis in the compounding effects of diabetes mellitus in periodontitis

摘要 控制不佳的糖尿病（DM）会加剧牙周炎（PD）的发展和进展。 此外，在不受控制的DM患者中管理PD仍然是一项临床挑战。事实上，PD 是糖尿病第六常见的并发症。然而，DM化合物 PD尚未完全了解，尽管炎症反应的增强起着核心作用。的主要 DM的炎症介质是CXCL 10。有趣的是，CXCL 10在PD中也起着重要作用。CXCL10 在牙周病组织和PD患者血清中表达水平较高。此外，委员会认为， 我们的实验室已经表明CXCL 10-CXCR 3轴是PD发展的基础。我们证明 当CXCL 10在小鼠中作用时，实验诱导的牙周骨丢失（EPD）显著减少， 受体CXCR 3缺失。此外，CXCR 3拮抗剂的全身和局部递送减弱EPD， 指出CXCL 10作为PD的潜在干预的目标。鉴于DM加重PD， CXCL 10作为DM和PD炎症介质的关键作用，我们假设CXCL 10在DM和PD的炎症介质中是中心的， 介导DM和PD的有害作用。因此，靶向CXCL 10-CXCR 3轴应改善CXCL 10-CXCR 3轴的表达。 DM在牙周组织中的有害作用，是牙周炎的潜在治疗策略。 管理未控制的DM患者。为了实现我们的目标，我们有两个具体目标（SA）。SA1： 通过缺失CXCL 10（SA 1a）并通过施用CXCL 10（SA 1a）来进一步阐明CXCL 10在牙周组织中的作用。 CXCL 10全身性（SA 1b）。SA 2：确定CXCR 3拮抗剂对牙周破坏的抑制作用 在患有DM的小鼠中。为此，我们将评估含有CXCR 3拮抗剂的纳米颗粒的局部递送， AMG-487可减轻DM对PD的影响。简而言之，将在小鼠中诱导DM，将产生EPD， AMG-487将以缓释纳米颗粒的形式局部给药。这些实验将提供证据- 在糖尿病患者牙周炎症中靶向CXCL 10-CXCR 3信号传导的主要证据。的 我们研究的长期目标是分析CXCL 10在糖尿病加重PD中的作用， 基金会开发一种新的治疗方法，以协助牙周病患者的治疗， 不受控制的糖尿病

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.