Regulation of bone loss by IL-23/IL-17A axis in inflammatory arthritis

描述(申请人提供)：大约5000万美国人(22%)患有某种形式的关节炎，据估计，随着全球人口老龄化，到2030年，6700万成年人将患有关节炎，其经济影响超过1280亿美元。尽管白细胞介素23(IL-23)参与了关节炎的发病机制，但其分子机制仍不清楚。自从IL-23对表达白介素17(Th17)的致病T辅助细胞的调节作用被发现以来，IL-23的直接作用在关节炎中的重要性就被掩盖了。为了强调它的重要性，我们建立了IL-23和IL-17A的基因转移模型，并利用这些模型建立了IL-23是关节炎的有效诱因，而不是IL-17A。从IL-23/IL-17A轴解剖IL-23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细胞和髓样细胞共同需要由ITAM介导的共刺激信号。ITAM是一个保守的信号基序，包含在跨膜适配器分子的细胞质结构域中，这些分子结合并传递存在于造血祖细胞中的各种免疫受体的信号。这些信号协调滑膜炎症和髓样细胞向骨吸收细胞的分化，称为破骨细胞。发现在炎症性关节炎中决定破骨细胞招募和激活的细胞和分子机制是预防这种致残条件的核心。对这些细胞和分子相互作用的详细了解将为关节炎的调节提供洞察力，可用于治疗干预。

DESCRIPTION (provided by applicant): About 50 million Americans (22%) suffer from some form of 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 signaling motif contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated and transmit signals from various immunoreceptors present in haematopoietic progenitors. These signals orchestrate synovial inflammation and differentiation of myeloid cells to bone resorbing cells called osteoclasts. 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.