Trained innate immunity and periodontitis-associated comorbidities

训练有素的先天免疫和牙周炎相关合并症

• 批准号: 10551226
• 负责人: Georgios Hajishengallis
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551226
• 关键词: Address; Affect; Arthritis; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cardiovascular Diseases; Cell Separation; Cells; Cellular Assay; Chromatin; Chronic; Chronic Disease; Data; Development; Disease; Epidemiology; Epigenetic Process; Future; Gene Expression; Hematopoietic stem cells; Immune; Immunologic Memory; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Interleukin-1 Receptors; Interleukin-1 beta; Investigation; Knowledge; Leukocytes; Ligature; Long-Term Effects; Mediating; Memory; Modification; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Oral; PTPRC gene; Periodontal Diseases; Periodontitis; Peripheral; Phenotype; Pre-Clinical Model; Predisposition; Procedures; Production; Proliferating; Readiness; Rheumatoid Arthritis; Role; Seminal; Signal Transduction; Stimulus; Study models; System; Systemic disease; Tamoxifen; Testing; Training; Transplantation; Transposase; chronic inflammatory disease; collagen antibody induced arthritis; comorbidity; congenic; cytokine; design; experimental study; holistic approach; inflammatory bone loss; insight; novel; novel therapeutic intervention; pharmacologic; progenitor; stem cells; systemic inflammatory response; therapeutic target; transcriptomics; transmission process

Project Summary Periodontal disease (PD) is a prevalent oral inflammatory condition that is epidemiologically associated with systemic disorders (comorbidities), such as, cardiovascular disease, rheumatoid arthritis, and type-2 diabetes. An independent association between PD and comorbidities remains even after adjustment for confounders. A possible factor contributing to this independent association is that PD can cause low-grade systemic inflammation, which may in turn influence comorbidities. The relationship between PD and systemic comorbidities is bidirectional in that systemic diseases can also promote susceptibility to PD. However, there is no known unifying causal mechanism that can explain how PD affects and is affected by comorbidities. To mechanistically explain the reciprocal association between PD and comorbid conditions, a novel hypothesis is proposed based on the recent concept that systemic inflammatory stimuli can cause epigenetic rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, which enables these cells to give rise to ‘trained’ myeloid cells that can respond more strongly to future stimuli. This concept represents a form of innate immune memory and is known as ‘trained innate immunity’ (TII). TII can be protective in infections but potentially detrimental, hence maladaptive, in inflammatory disorders. Thus, given that chronic inflammatory diseases are – in large part – driven by the action of inflammatory myeloid cells, inflammation-driven transcriptomic and epigenetic alterations in their bone marrow progenitors are likely to influence the initiation or the progression of different chronic inflammatory disorders that emerge as comorbidities. This project involves investigation of the comorbidity of PD with another inflammatory bone loss disorder, rheumatoid arthritis. The overarching hypothesis is that maladaptive TII constitutes a mechanistic basis for the comorbid connection of PD and arthritis, which are studied using validated preclinical models, ligature-induced PD (LIP) and collagen antibody-induced arthritis (CAIA), respectively. The objective of Aim 1 is to show that inflammation-adapted HSPCs in the bone marrow mediates the comorbid association of PD and inflammatory arthritis. That the proposed maladaptive effect is mediated by inflammation-adapted (‘trained’) HSPCs will be tested by bone marrow transplantation experiments. Aim 2 was designed to investigate whether experimental PD induces transmissible epigenetic modifications in bone marrow progenitors towards a maladaptive inflammatory phenotype that underlies the development of inflammatory comorbidities. Further studies are proposed to show that interleukin-1β acts on HSPCs to mediate LIP-induced trained myelopoiesis and increased disease activity (Aim 3). If successful, this project will provide a unifying network for and mechanistic insights into the interconnection of inflammatory comorbidities and maladaptive TII in the bone marrow. Such conceptual framework could also provide a platform for novel therapeutic interventions targeting inflammatory comorbidities via pharmacological modulation of TII.

项目概要 牙周病 (PD) 是一种常见的口腔炎症性疾病，在流行病学上与以下因素相关： 全身性疾病（合并症），例如心血管疾病、类风湿性关节炎和 2 型糖尿病。 即使在调整混杂因素后，PD 与合并症之间仍然存在独立关联。一个 造成这种独立关联的可能因素是 PD 可导致低级别系统性 炎症，进而可能影响合并症。 PD与全身合并症的关系 是双向的，因为全身性疾病也可以促进对PD的易感性。然而，尚无已知的 统一的因果机制可以解释 PD 如何影响合并症以及如何受合并症影响。机械地 为了解释 PD 与合并症之间的相互关联，提出了一个新的假设 关于全身炎症刺激可引起造血干表观遗传重新布线的最新概念 骨髓中的祖细胞（HSPC），使这些细胞能够产生“训练有素的”骨髓细胞 可以对未来的刺激做出更强烈的反应。这个概念代表了先天免疫记忆的一种形式 被称为“训练有素的先天免疫”（TII）。 TII 对感染具有保护作用，但也可能有害，因此 适应不良，炎症性疾病。因此，鉴于慢性炎症性疾病在很大程度上是 由炎症性骨髓细胞、炎症驱动的转录组和表观遗传改变的作用驱动 在他们的骨髓祖细胞中可能影响不同慢性疾病的发生或进展 作为合并症出现的炎症性疾病。该项目涉及PD合并症的调查 与另一种炎症性骨质流失疾病——类风湿性关节炎有关。总体假设是 适应不良的 TII 构成了 PD 和关节炎共病联系的机制基础，对此进行了研究 使用经过验证的临床前模型、结扎诱导的 PD (LIP) 和胶原蛋白抗体诱导的关节炎 (CAIA)， 分别。目标 1 的目标是证明骨髓中的炎症适应 HSPC 介导 PD 和炎症性关节炎的共病关联。所提出的适应不良效应是由 炎症适应（“训练”）的 HSPC 将通过骨髓移植实验进行测试。目标 2 是 旨在研究实验性 PD 是否会诱导骨髓中可遗传的表观遗传修饰 祖细胞向适应不良的炎症表型发展，这是炎症发展的基础 合并症。进一步的研究表明，IL-1β 作用于 HSPC，介导 LIP 诱导的 训练骨髓细胞生成并增加疾病活动性（目标 3）。如果成功，该项目将提供一个统一的 炎症合并症与适应不良 TII 之间相互联系的网络和机制见解 在骨髓中。这种概念框架还可以为新型治疗干预提供平台 通过 TII 的药理调节来治疗炎症合并症。