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.

项目摘要 牙周疾病（PD）是一种普遍的口腔炎症病，在流行病学上与 全身性疾病（合并症），例如心血管疾病，类风湿关节炎和2型糖尿病。 即使在调整了混杂因素之后，PD与合并症之间的独立关联仍然存在。一个 导致这种独立关联的可能因素是PD会引起低级全身性 炎症，这可能会影响合并症。 PD与系统合并症之间的关系 是双向的，因为系统性疾病也可以促进对PD的敏感性。但是，没有已知的 统一因果机制，可以解释PD如何影响和受合并症的影响。机械 解释PD与合并条件之间的相互关联，提出了一个新的假设 在最近的概念上，系统性炎症刺激会导致造血茎的表观遗传重新布线 骨髓中的祖细胞（HSPC），这使这些细胞能够产生“训练”的髓样细胞 这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可以在感染中受到保护，但可能有害，因此 适应不良的炎症性疾病。鉴于慢性炎症性疾病在很大程度上是 受炎症性髓样细胞的作用，炎症驱动的转录组和表观遗传学改变的驱动 在他们的骨髓中，祖细胞可能会影响不同慢性的倡议或进展 炎症性疾病作为合并症。该项目涉及调查PD合并症 伴有另一种炎症性骨质疾病，类风湿关节炎。总体假设是 适应不良的TII构成了PD和关节炎合并连接的机械基础，这是研究的 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的目的是表明骨髓培养基中适应炎症的HSPC PD的合并关联和炎症性关节炎。提出的不良适应作用是由 适应炎症的HSPC将通过骨髓移植实验进行测试。 AIM 2是 旨在研究实验性PD是否诱导骨髓中的可传播表观遗传修饰 祖先对不良适应性炎症表型的发展，该表型是炎症发展的基础 合并症。提出进一步的研究表明，白细胞介素1β作用于HSPC，以介导唇部诱导 训练有素的脊髓虫和增加疾病活动（AIM 3）。如果成功，该项目将提供一个统一的 炎症合并症和适应不良TII的互连的网络和机械洞察力 在骨髓中。这种概念框架还可以为新型热干预提供平台 通过TII的药物调制来靶向炎症合并症。