Ligation of TLR7 promotes joint inflammation and bone loss in RA.

TLR7 的连接会促进 RA 中的关节炎症和骨质流失。

• 批准号: 9551960
• 负责人: SHIVA SHAHRARA
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9551960
• 关键词: Address; Adult; Affect; African American; Anti-inflammatory; Arthralgia; Arthritis; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Biogenesis; Biological Response Modifier Therapy; Blood Circulation; Bone Radiology; Bone Resorption; Cartilage; Cell Differentiation process; Cells; Chronic; Clinic; Collagen-Induced Arthritis; Connective Tissue Diseases; Data; Development; Disease; Disease Progression; Event; Experimental Arthritis; Family; Fostering; Friends; Genes; Hispanics; Human; Impairment; Infiltration; Inflammatory; Inflammatory Arthritis; Interleukin-17; Interleukin-6; Interruption; Joints; Lead; Ligands; Ligation; Link; Mature Bone; Mediating; MicroRNAs; Microarray Analysis; Military Personnel; Molecular; Mus; Myeloid Cells; Myeloproliferative disease; Osteoclasts; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Process; RNA; Research; Rheumatoid Arthritis; Role; Services; Severities; Source; Specimen; Synovial Fluid; Synovitis; System; T-Lymphocyte; TLR7 gene; TNF gene; Time; Tissues; United States; Validation; Veterans; War; Wild Type Mouse; Woman; Work; base; bone; bone erosion; bone loss; cell motility; cell type; disability; exosome; improved; in vivo; joint destruction; macrophage; member; microvesicles; monocyte; new therapeutic target; novel; osteoclastogenesis; peripheral blood; polarized cell; public health relevance; recruit; response; trafficking

DESCRIPTION (provided by applicant): In the United States, 2.5 million people have rheumatoid arthritis (RA). RA is a chronic inflammatory autoimmune disorder that starts in the young to middle adult years and may lead to complete joint destruction if untreated. There is no cure for RA at present and up to 40% of RA patients do not respond to anti-TNF agents or other biological treatments due to lack of efficacy or intolerability therefore novel treatment targets are urgently needed. Findings that lea to novel treatments can benefit all active and retired military and VA members with RA, as well as their families and friends who may suffer from RA. Effective and improved treatments through identification of cascades that modulate RA synovial inflammation and bone erosion will allow active duty members to remain longer in service and will also relieve joint pain and disability in retired Veterans. The quantity of RA synovial CD68+ macrophages is reduced in positive response to therapy concurrent with reduction in disease activity therefore the number of myeloid cells closely correlates with radiological bone damage, joint pain and inflammation. Yet, the mechanism that drives RA myeloid cell differentiation to proinflammatory macrophages or mature bone eroding osteoclasts is undefined. To address this vital issue, highly modulated genes were identified in RA compared to normal myeloid cells employing microarray analysis. In validation of the microarray data, we found that TLR7 is one of the most highly upregulated genes in RA synovial fluid and RA peripheral blood myeloid cells compared to normal peripheral blood myeloid cells. We discovered a novel TLR7 endogenous ligand in RA synovial fluid and documented that this ligand is strongly capable of transforming the newly recruited na�ve myeloid cells into inflammatory macrophage phenotype. We also found that the osteoclast maturation process is associated with increased TLR7 expression and that the enhanced response to TLR7 endogenous ligand can provoke differentiation of fully mature RA osteoclasts. Based on the supportive data, we hypothesize that the na�ve RA myeloid cells are remodeled to proinflammatory macrophages and mature osteoclasts through TLR7 ligation. Therefore disruption of TLR7 binding to its endogenous ligand will resolve RA and experimental arthritis by dysregulating the development of inflammatory macrophages and mature osteoclasts. We uncover for the first time, a novel TLR7 endogenous ligand, and propose to determine the origination and the underlying mechanism by which ligation of this endogenous ligand to TLR7 contributes to RA pathogenesis and how this cascade of events is interconnected to the inflammatory RA network. Finally we will document whether interruption in TLR7 ligation to its endogenous ligand can be used as a promising new therapeutic target in RA.

描述（由申请人提供）： 在美国，有250万人患有类风湿性关节炎（RA）。类风湿关节炎是一种慢性炎症性自身免疫性疾病，开始于年轻人到中年人，如果不治疗，可能导致关节完全破坏。目前，RA无法治愈，高达40%的RA患者因缺乏疗效或不耐受而对抗TNF药物或其他生物治疗无反应，因此迫切需要新的治疗靶点。研究结果表明，莱亚新的治疗方法可以受益于所有积极和退休的军事和退伍军人协会成员与类风湿关节炎，以及他们的家人和朋友谁可能患有类风湿关节炎。通过识别调节类风湿关节炎滑膜炎症和骨质侵蚀的级联反应，有效和改进的治疗将使现役成员能够保持更长的服务时间，并将缓解退休退伍军人的关节疼痛和残疾。 RA滑膜CD68+巨噬细胞的数量在对治疗的阳性反应中减少，同时疾病活动减少，因此骨髓细胞的数量与放射性骨损伤、关节疼痛和炎症密切相关。然而，驱动RA骨髓细胞分化为促炎性巨噬细胞或成熟骨侵蚀破骨细胞的机制尚不明确。为了解决这一重要问题，采用微阵列分析，与正常骨髓细胞相比，在RA中鉴定出高度调节的基因。在微阵列数据的验证中，我们发现与正常外周血骨髓细胞相比，TLR7是RA滑液和RA外周血骨髓细胞中最高度上调的基因之一。我们在RA滑液中发现了一种新的TLR7内源性配体，并证明这种配体能够将新招募的幼稚骨髓细胞转化为炎性巨噬细胞表型。我们还发现，破骨细胞的成熟过程与增加TLR7的表达，并增强对TLR7内源性配体的反应，可以引起完全成熟的RA破骨细胞的分化。 基于支持性数据，我们假设幼稚RA骨髓细胞通过TLR7连接重塑为促炎性巨噬细胞和成熟破骨细胞。因此，破坏TLR7与其内源性配体的结合将通过炎症巨噬细胞和成熟破骨细胞的发育失调来解决RA和实验性关节炎。我们首次发现了一种新的TLR7内源性配体，并提出确定这种内源性配体与TLR7的连接有助于RA发病机制的起源和潜在机制，以及这种级联事件如何与炎症性RA网络相互联系。最后，我们将记录TLR7连接到其内源性配体的中断是否可以用作RA中有前途的新治疗靶点。