Neutrophil homeostasis and periodontitis: Novel concepts and treatments

 描述（由申请人提供）：牙周炎是一种导致牙齿支持组织（牙周组织）破坏的炎性疾病，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个体，如I型白细胞粘附缺陷症（LAD-I），在生命早期发展为严重的牙周炎。了解罕见单基因疾病（如LAD-I）的致病机制很重要，原因有两个：首先，有效治疗患有这些特定疾病的患者;其次，这些疾病代表了了解人类生物学的真实模型，并为常见疾病提供了重要见解。与LAD-I相关的牙周炎历史上归因于牙周感染的中性粒细胞监视受损;然而，它对抗生素和/或牙齿相关生物膜的机械去除无反应，导致乳牙和恒牙过早脱落，并且可能对受影响的儿童产生严重的不良心理和功能后果。该项目的总体目标是确定与LAD-I相关的牙周炎（“LAD-I牙周炎”）的基本潜在机制，并提出合理的新治疗方案。最重要的假设是，LAD-I牙周炎是由骨吸收细胞因子IL-17的失调过度表达引起的，这是由于被称为“骨吸收抑制剂”的稳态机制的破坏。这是涉及IL-23-IL-17轴的调节反馈环，其协调组织中的中性粒细胞募集和嗜中性粒细胞增多与骨髓中的中性粒细胞产生。这一总体假设得到了充分的初步证据的支持，例如，数据显示，在人LAD-I患者和相关的LAD-I小鼠模型中，IL-23和IL-17显著升高，而在成人型慢性牙周炎中检测到这些细胞因子的水平相当低。该提案包括四个具体目标，重点是基于小鼠模型的机制和干预研究。在目的1中，提出用具有迁移能力的中性粒细胞重建LAD-1小鼠恢复正常的IL-23和IL-17水平并抑制骨丢失。目的2：研究凋亡中性粒细胞吞噬作用的抑制是否能复制LAD-I型牙周炎的表型。目的3是确定合成激动剂诱导的肝X受体（通常在嗜中性粒细胞增多症下游的巨噬细胞中活化）的活化是否补偿了凋亡嗜中性粒细胞的缺乏并恢复了LAD-I小鼠牙龈中的IL- 23/IL-17调节。目的4涉及通过使用靶向IL-23-IL-17通路的小分子化合物来开发LAD-I牙周炎的新治疗方法。因此，这种应用提供了对LAD-I牙周炎（以及可能伴有中性粒细胞募集受损的其他疾病）机制的全新见解，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.