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)。 RA 是一种慢性炎症性自身免疫性疾病，始于青年至中年，如果不及时治疗，可能会导致关节完全破坏。目前，RA 尚无治愈方法，高达 40% 的 RA 患者由于缺乏疗效或无法耐受而对抗 TNF 药物或其他生物治疗没有反应，因此迫切需要新的治疗靶点。带来新疗法的研究结果可以使所有患有类风湿性关节炎的现役和退役军人和退伍军人管理局成员以及他们可能患有类风湿性关节炎的家人和朋友受益。通过识别调节 RA 滑膜炎症和骨质侵蚀的级联，有效和改进的治疗方法将使现役军人能够延长服役时间，并减轻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积极反应中减少，同时疾病活动度降低，因此骨髓细胞的数量与放射学骨损伤、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巨噬细胞或成熟骨质侵蚀破骨细胞的机制尚不清楚。为了解决这个重要问题，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。在验证微阵列数据时，我们发现与正常外周血骨髓细胞相比，TLR7 是 RA 滑液和 RA 外周血骨髓细胞中表达最高度上调的基因之一。我们在 RA 滑液中发现了一种新型 TLR7 内源性配体，并证明该配体具有很强的能力将新招募的幼稚骨髓细胞转化为炎症巨噬细胞表型。我们还发现破骨细胞成熟过程与 TLR7 表达增加相关，并且对 TLR7 内源配体的增强反应可以激发完全成熟的 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 连接被重塑为促炎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调节炎症巨噬细胞和成熟破骨细胞的发育来解决RA和实验性关节炎。我们首次发现了一种新型 TLR7 内源性配体，并提出确定这种内源性配体与 TLR7 的连接导致 RA 发病机制的起源和潜在机制，以及这一系列事件如何与炎症性 RA 网络相互关联。最后，我们将证明中断 TLR7 与其内源配体的连接是否可以作为 RA 有希望的新治疗靶点。