Novel Regulators of Inflammatory Arthritis and Bone Erosion

 描述(申请人提供)：先天性免疫细胞调节失调被认为是系统性青少年特发性关节炎(SJIA)的主要驱动因素。巨噬细胞衍生的细胞因子，特别是IL-1和IL-6，在sJIA的炎症环境中占主导地位[4]。差异化 在前生物时代，巨噬细胞进入骨吸收破骨细胞(OCS)是导致高达50%的sJIA患者[5]持续侵蚀性关节炎的原因，并且仍然是相当一部分患者的问题(CARRAnet注册数据、准备中的手稿、Mellins及其同事)。此外，在sJIA的一种严重的、可能致命的并发症中观察到巨噬细胞的过度激活，称为巨噬细胞激活综合征(MAS)，在sJIA的儿童中发生高达30%[6]。因此，巨噬细胞似乎是sJIA发病机制中的中心角色。不幸的是，目前sJIA治疗的主要挑战是找到既能有效治疗炎症反应又能有效治疗其溶骨作用而又不会引起整体免疫抑制效应的联合治疗方法。一种有效的方法是选择性地针对控制巨噬细胞的炎症和骨吸收效应的信号分子。我们发现TMEM178是一种跨膜蛋白，在体内外对巨噬细胞的激活和OC的形成起负调节作用，其功能尚未见报道。与健康对照组相比，sJIA患者血浆刺激的人单核细胞中TMEM178水平下降的观察支持了这一发现的意义。在机制上，TMEM178定位于内质网，在那里它与钙传感器STIM1结合，从而限制巨噬细胞和OCS的细胞内钙流动。根据我们的初步发现，我们假设在sJIA过程中，TMEM178需要通过调节细胞内钙信号来抑制炎性细胞因子的产生和OC的形成。因此，我们建议：目的1.在炎性关节炎模型和sJIA标本中确定TMEM178在巨噬细胞活化中的重要性。目的2.确定TMEM178在破骨细胞活化中的作用。目的3.阐明TMEM178调控巨噬细胞和破骨细胞反应的机制。总之，考虑到sJIA血浆处理的人单核细胞TMEM178 mRNA表达水平降低，了解TMEM178抑制巨噬细胞激活和OC形成的机制可能会导致开发治疗sJIA的新策略。本研究结果表明，TMEM178可能是一个与sJIA及其并发症MAS和相关侵蚀性疾病相关的新基因，TMEM178靶向治疗可能是一种新的治疗方法。

 DESCRIPTION (provided by applicant): Dysregulation of innate immune cells is thought to be the main driver of systemic Juvenile Idiopathic Arthritis (sJIA). Macrophage-derived cytokines, particularly IL-1 and IL-6, predominate within the inflammatory milieu in sJIA [4]. Differentiation of macrophages into bone resorbing osteoclasts (OCs) was responsible for persistent erosive arthritis in up to 50% of sJIA patients [5] in the pre-biologic era, and remains an issue for a significant subset of patients (CARRAnet registry data, manuscript in preparation, Mellins and colleagues). In addition, excessive activation of macrophages is observed in a severe, potentially lethal, complication of sJIA, termed macrophage activation syndrome (MAS), occurring in up to 30% of children with sJIA [6]. Thus, macrophages appear to be central players in the pathogenesis of sJIA. Unfortunately, finding effective combined treatments of both inflammatory reactions and their osteolytic consequences, without inducing global immune suppressive effects, represents the major challenge of current sJIA therapies. An efficacious approach would be to selectively target the signaling molecules controlling the inflammatory and bone resorptive effects of macrophages. We identified TMEM178, a transmembrane protein whose function has not been reported, to be a negative regulator of macrophage activation and OC formation in vitro and in vivo. The significance of this finding is buttressed by the observation that TMEM178 levels decrease in human monocytes stimulated with plasma from sJIA patients compared to healthy controls. Mechanistically, TMEM178 localizes in the endoplasmic reticulum where it binds to the calcium sensor STIM1, thereby limiting intracellular calcium fluxes in macrophages and OCs. Based on our preliminary findings we hypothesize that during sJIA, TMEM178 is required to restrain inflammatory cytokine production and OC formation via modulation of intracellular calcium signaling. Therefore, we propose to: Aim 1. Determine the importance of TMEM178 in macrophage activation in inflammatory arthritis models and sJIA samples. Aim 2. Determine the role of TMEM178 in osteoclast activation. Aim 3. Elucidate the mechanism by which TMEM178 controls macrophage and osteoclast responses. In sum, considering the reduced TMEM178 mRNA expression levels in human monocytes treated with sJIA plasma, understanding the mechanism by which TMEM178 restrains macrophage activation and OC formation could lead to the development of new strategies to treat sJIA. The results of this study could position TMEM178 as a novel gene related to development of sJIA, its complication MAS and associated erosive disease, and TMEM178 targeting may be a novel therapeutic approach.