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

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，据估计， 全球人口老龄化，到2030年将有6700万成年人患有关节炎，其经济影响更大 超过1280亿美元。尽管白细胞介素23(IL-23)与关节炎的发病机制有关， 其分子机制尚不清楚。自从发现IL-23对致病T辅助细胞的调节以来 表达白细胞介素17(Th17)的细胞IL-23的直接作用在关节炎中的重要性被遮盖了。 为了强调其重要性，我们建立了IL-23和IL-17A的基因转移模型，并使用这些模型 确定IL-23是关节炎的有效诱因，独立于IL-17A。从IL-23中分离IL-23 23/IL-17A轴使我们能够揭示以前被忽视的髓系细胞激活的新机制。 我们发现，IL-23不依赖于Th17细胞，而是通过激活髓系细胞来诱导关节炎。T 细胞和髓系细胞共同需要由ITAM介导的共刺激信号。ITAM是 包含在跨膜接头分子的细胞质结构域中的保守信号基序 关联并传递存在于造血祖细胞中的各种免疫受体的信号。我们有 发现IL-23诱导MDL-1受体的激活和募集，MDL-1受体协调滑膜和 皮肤炎症分别通过激活破骨细胞和中性粒细胞。发现蜂窝和 炎症性关节炎中决定破骨细胞募集和激活的分子机制是核心 以防止这种禁用状态。对这些细胞和分子相互作用的详细了解将 对关节炎的调控提供可用于治疗干预的见解。

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.