Neutrophil homeostasis and periodontitis: Novel concepts and treatments

 描述(申请人提供)：牙周炎是一种炎症性疾病，导致牙齿支持组织(牙周组织)的破坏，通常影响成年人。然而，患有影响中性粒细胞向牙周组织募集的疾病的人，如I型白细胞黏附缺陷(LAD-I)，在生命早期就会患上严重的牙周炎。了解罕见的单基因疾病(如LAD-I)的致病机制很重要，原因有两个：第一，对于患有这些特定疾病的患者进行有效治疗；第二，这些疾病代表着理解人类生物学的真实模型，并为常见疾病提供关键的见解。与LAD-I相关的牙周炎历来被认为是由于中性粒细胞对牙周感染的监测受损所致；然而，它对抗生素和/或机械去除牙齿相关生物膜没有反应，导致乳牙和恒牙过早丧失，并可能对受影响的儿童产生严重的不利心理和功能后果。本项目的总体目标是确定与LAD-I相关的牙周炎的基本潜在机制(S)，并提出合理的新的治疗方案。最重要的假设是LAD-I牙周炎是由骨吸收细胞因子IL-17的异常过度表达引起的，这是由于一种被称为中性粒细胞稳态的机制被破坏而引起的。这是一个涉及IL-23-IL-17轴的调节反馈回路，它协调组织中中性粒细胞的募集和泡腾作用与骨髓中中性粒细胞的产生。最重要的假设得到了大量初步证据的支持，例如，数据显示，在人类LAD-I患者和相关的LAD-I小鼠模型中，IL-23和IL-17水平显著升高，而在成人型慢性牙周炎中，这些细胞因子的水平要低得多。该建议包括四个具体目标，重点是基于小鼠模型的机制和干预研究。在目标1中，建议重建具有迁移能力的中性粒细胞的LAD-I小鼠，恢复正常的IL-23和IL-17水平，并抑制骨丢失。目的研究抑制凋亡中性粒细胞吞噬(泡出)是否复制LAD-I牙周炎的表型。目的3是确定合成激动剂诱导的肝X受体(通常在中性粒细胞泡出下游的巨噬细胞中激活)是否可以弥补LAD-I小鼠牙龈中中性粒细胞凋亡的缺失，并恢复IL-23/IL-17的调节。目的4通过使用以IL-23-IL-17通路为靶点的小分子化合物，开发治疗LAD-I牙周炎的新方法。因此，这项应用为LAD-I牙周炎(可能还有其他中性粒细胞募集受损的疾病)的发病机制提供了一个全新的见解，并有可能导致创新的宿主调节方法，从而彻底改变受影响个体的牙周治疗。

 DESCRIPTION (provided by applicant): Periodontitis is an inflammatory disease that causes destruction of the tooth-supporting tissues (periodontium) and typically affects adults. However, individuals with disorders affecting neutrophil recruitment to the periodontium, such as leukocyte adhesion deficiency Type I (LAD-I), develop severe periodontitis early in life. Understanding the pathogenic mechanisms of rare monogenic diseases, such as LAD-I, is important for two reasons: First, for effective treatment of patients with these specific disorders; second, these disorders represent real-life models to understand human biology and provide critical insights into common diseases. Periodontitis associated with LAD-I has been historically attributed to impaired neutrophil surveillance of the periodontal infection; however, it is unresponsive to antibiotics and/or mechanical removal of the tooth- associated biofilm, leads to premature loss of primary and permanent teeth, and can have serious adverse psychological and functional consequences in affected children. The overall objective of this project is to identify the fundamental underlying mechanism(s) of periodontitis associated with LAD-I ("LAD-I periodontitis") and to propose rational novel treatment options. The overarching hypothesis is that LAD-I periodontitis is caused by dysregulated overexpression of the bone-resorptive cytokine IL-17 due to the disruption of a homeostatic mechanism known as the "neutrostat". This is a regulatory feedback loop involving the IL-23-IL-17 axis that coordinates neutrophil recruitment and efferocytosis in tissues with neutrophil production in the bone marrow. The overarching hypothesis is supported by ample preliminary evidence, e.g., data revealing profound elevation of IL-23 and IL-17 in human LAD-I patients and in relevant mouse models of LAD-I, whereas considerably lower levels of these cytokines are detected in adult-type chronic periodontitis. This proposal comprises four specific aims and focuses on mouse model-based mechanistic and intervention studies. In Aim 1, it is proposed that that reconstitution of LAD-I mice with transmigration-competent neutrophils restores normal IL-23 and IL-17 levels and inhibits bone loss. Aim 2 investigates whether inhibition of apoptotic neutrophil phagocytosis (efferocytosis) replicates the LAD-I periodontitis phenotype. Aim 3 is to determine whether synthetic agonist-induced activation of liver X receptor (normally activated in macrophages downstream of neutrophil efferocytosis) compensates for the lack of apoptotic neutrophils and restores IL- 23/IL-17 regulation in the gingiva of LAD-I mice. Aim 4 involves the development of novel therapeutic approaches to LAD-I periodontitis through the use of small-molecule compounds targeting the IL-23-IL-17 pathway. This application, therefore, offers a fundamentally new insight into the mechanism of LAD-I periodontitis (and perhaps other disorders with impaired neutrophil recruitment) and has the potential to lead to innovative host-modulation approaches that can revolutionize the periodontal treatment of affected individuals.