The IL-23/IL-17 Axis in Inflammatory Arthritis

炎症性关节炎中的 IL-23/IL-17 轴

基本信息

批准号：
10077832
负责人：
Iannis Elias Adamopoulos
金额：
$ 1.77万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077832
关键词：
Adoptive Transfer Adult American Animal Model Antibodies Arthritis Autoimmunity Binding Biological Markers Cell Differentiation process Cell Surface Receptors Cells Cellular biology Clinical Clinical Data Cytoplasmic Tail Data Development Disease Disease Progression Disputes Dissection Flow Cytometry Functional disorder Funding Gene Expression Profiling Gene Transfer Genes Helper-Inducer T-Lymphocyte Hematopoietic stem cells Histology Human ITAM ITGAM gene Image Analysis Immunologics In Vitro Individual Inflammation Inflammatory Arthritis Interleukin-17 Joints Knock-in Mouse Lectin Lymphoid Lymphoid Cell Mediating Modeling Molecular Molecular Target Mus Myelogenous Myeloid Cell Activation Myeloid Cells Myelopoiesis Natural Immunity Osteoclasts Pathogenesis Pathogenicity Pathologic Pathology Patients Phenotype Population Proteins Psoriatic Arthritis Regulation Reporter Research Personnel Role Sampling Signal Transduction Skin Spondylarthropathies T-Lymphocyte TYROBP gene Testing Therapeutic Intervention Time Transducers Transgenic Mice Transmembrane Domain aging population base bone bone loss cellular targeting clinically significant cohort cytokine digital imaging economic impact enthesitis experimental study in vitro Assay in vivo insight interleukin-23 mutant nanoprobe neutrophil novel premature prevent programs receptor recruit skin organogenesis transcriptome transcriptome sequencing γδ T cells

项目摘要

Project Summary/Abstract About 50 million Americans (22%) suffer from some form of inflammatory arthritis and estimates are that, with the aging population worldwide, 67 million adults will have arthritis by 2030 with an economic impact higher than $128 billion dollars. Although interleukin-23 (IL-23) has been implicated in the pathogenesis of arthritis, the molecular mechanisms remain unknown. Since the discovery of IL-23 regulation of pathogenic T helper cells that express interleukin-17 (Th17) the importance of direct actions of IL-23 in arthritis is overshadowed. To highlight its importance we developed gene-transfer models of IL-23 and IL-17A and using these models we established that IL-23 is a potent inducer of arthritis, independently of IL-17A. Dissection of IL-23 from the IL- 23/IL-17A axis has allowed us to uncover novel mechanisms of myeloid cell activation previously overlooked. We identified that IL-23 induces arthritis independently of Th17 cells and through activation of myeloid cells. T cells and myeloid cells share a requirement for costimulatory signals that are mediated by ITAMs. The ITAM is a conserved signalling motif contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated and transmit signals from various immunoreceptors present in haematopoietic progenitors. We have identified that IL-23 induces the activation and recruitment of MDL-1 receptor that orchestrates synovial and skin inflammation via the activation of osteoclasts and neutrophils respectively. Discovering the cellular and molecular mechanisms that dictate recruitment and activation of osteoclasts in inflammatory arthritis is central to preventing this disabling condition. Detailed understanding of these cellular and molecular interactions will yield insights into regulation of arthritis that can be exploited for therapeutic interventions.

项目摘要/摘要约有5000万美国人（22％）患有某种形式的炎症性关节炎，估计是，有全球衰老的人口年龄，有6700万成年人将于2030年患有关节炎，经济影响更高超过1280亿美元。尽管白介素23（IL-23）与关节炎的发病机理有关分子机制仍然未知。由于发现IL-23病原T辅助器的调节表达白细胞介素17（TH17）的细胞IL-23在关节炎中的直接作用的重要性被掩盖了。为了强调其重要性，我们开发了IL-23和IL-17A的基因转移模型，并使用这些模型我们确定IL-23是关节炎的有效诱导剂，独立于IL-17A。从IL-解剖IL-23 23/il-17a轴使我们能够发现以前被忽略的髓样细胞激活的新机制。我们确定IL-23独立于TH17细胞和通过激活髓样细胞诱导关节炎。 t 细胞和髓样细胞对ITAM介导的共刺激信号的需求。 Itam是跨膜适配器分子的细胞质结构域中包含的保守信号基序是来自造血祖细胞中存在的各种免疫受体的相关和传输信号。我们有确定IL-23诱导了策划滑膜和的MDL-1受体的激活和募集皮肤炎症分别通过破骨细胞和中性粒细胞的激活。发现细胞和炎症性关节炎中决定募集和激活破骨细胞的分子机制是中心防止这种残疾状况。对这些细胞和分子相互作用的详细理解将对可以利用治疗干预措施的关节炎调节的见解。