Neutrophil homeostasis and periodontitis: Novel concepts and treatments

中性粒细胞稳态和牙周炎：新概念和治疗

• 批准号: 9357605
• 负责人: Georgios Hajishengallis
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357605
• 关键词: Adhesions; Adult; Affect; Agonist; Alveolar Bone Loss; Antibiotics; Antibodies; Apoptotic; Blood Circulation; Bone Marrow; Child; Clinical; Data; Development; Digoxin; Disease; Employee Strikes; Etiology; Excision; Exhibits; Feedback; Gingiva; Health; Homeostasis; Human; Human Biology; ITGB2 gene; Immunologic Deficiency Syndromes; Impairment; Individual; Inflammatory; Interleukin-17; Intervention Studies; Lead; Leukocyte Adhesion Deficiency; Life; Link; Liver X Receptor; Mechanics; Mediating; Mendelian disorder; Microbial Biofilms; Modeling; Mus; Mutation; Neutrophil Infiltration; Orphan; Pathogenicity; Pathway interactions; Patients; Periodontal Infection; Periodontitis; Periodontium; Peripheral; Phagocytes; Phagocytosis; Phenotype; Pre-Clinical Model; Process; Production; Receptor Activation; Receptor Signaling; Recruitment Activity; Regulation; Signal Transduction; Signaling Molecule; Tissues; Tooth structure; Tretinoin; Wild Type Mouse; base; bone; bone loss; cytokine; deciduous tooth; effective therapy; experimental study; inhibitor/antagonist; innovation; insight; interleukin-23; macrophage; mouse model; neutrophil; novel; novel therapeutic intervention; novel therapeutics; overexpression; permanent tooth; premature; prevent; psychologic; public health relevance; receptor; reconstitution; small molecule; small molecule therapeutics; trafficking; transcription factor

 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.

 描述（由适用提供）：牙周炎是一种炎症性疾病，会造成牙齿支持组织（牙周）的破坏，通常会影响成年人。但是，患有影响中性粒细胞募集到牙周的疾病的人，例如白细胞粘附缺乏I型（LAD-I），生命的早期就会出现严重的牙周炎。了解罕见单基因疾病（例如LAD-I）的致病机制很重要，原因有两个：首先，用于有效治疗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并提供对常见疾病的批判性见解的现实模型。与LAD-I相关的牙周炎历史上一直归因于牙周感染的中性粒细胞监测受损。但是，它对抗生素和/或机械去除牙齿相关的生物膜无反应，导致原发性和永久牙齿的过早丧失，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。该项目的总体目的是确定与LAD-I（“ LAD-I牙周炎”）相关的牙周炎的基本基本机制，并提出合理的新型治疗选择。总体假设是，由于骨化性细胞因子IL-17的过度表达失调引起的LAD-I牙周炎，由于稳态机制被称为“中性稳定器”，因此引起的骨骼敏感性细胞因子IL-17。这是一个涉及IL-23-IL-17轴的调节反馈回路，可在骨髓中嗜中性粒细胞产生的组织中互补的嗜中性粒细胞募集和肿瘤性。总体假设得到了足够的初步证据的支持，例如，人类LAD-I患者以及LAD-I的相关小鼠模型中的IL-23和IL-17的数据揭示了IL-23和IL-17的高度升高，而在成人慢性牙周炎中发现了这些细胞因子的较低水平。该提案包括四个特定的目的，并专注于基于小鼠模型的机械和干预研究。在AIM 1中，有人提出，具有传播能力中性粒细胞的LAD-I小鼠的重建会恢复正常的IL-23和IL-17水平，并抑制骨质流失。 AIM 2研究了抑制凋亡中性粒细胞的AIM 3是否是确定合成激动剂诱导的肝脏X受体激活（通常在中性粒细胞效率下降的巨噬细胞中激活）是否补偿缺乏凋亡性嗜中性粒细胞，并在Lad-imice中恢复IL-23/IL-17调节。 AIM 4涉及通过使用针对IL-23-IL-17途径的小分子化合物来开发新型LAD-I牙周炎的治疗方法。因此，该应用从根本上提供了对LAD-I牙周炎机制（以及可能受损中性粒细胞招募受损的其他疾病）的新见解，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。