Cyr61/CCN1蛋白通过上调巨噬细胞炎症因子表达参与成人斯蒂尔病发病的机制研究

Adult-onset Still’s disease (AOSD) is a rare inflammatory disease characterized by the classical triad of daily fever, arthritis, and typical salmon-colored rash. Although the pathogenesis is not fully understood, it is generally believed that the excessive activation of macrophages and expression of large amounts of inflammatory cytokines (such as IL-1β, IL-6, IL-18 and TNF-α, etc.) are involved in the development of AOSD. As a secreted extracellular matrix protein, Cyr61 (CCN1) has a role in mediating cell adhesion and in inducing cell migration, which is closely related to cell proliferation, neovascularization, and tumor formation. Furthermore, accumulating research has indicated that Cyr61 acts as a pro-inflammatory factor in the development of inflammatory and autoimmune diseases such as rheumatoid arthritis and psoriasis by enhancing the production of cytokines. However, it is unknown whether Cyr61 has a role in the pathogenesis of AOSD. In the current study, we found that the Cyr61 expression was upregulated in the peripheral blood of AOSD patients. Given that Cyr61 could promote inflammatory cytokines expression of IL-1β, IL-6 and TNF-α, we supposed that Cyr61 may contribute to the inflammatory microenvironment of AOSD. Thus, this project is aimed at analyzing the expression pattern of Cyr61 in peripheral blood of AOSD patients, exploring the profiles and signaling pathways of inflammatory cytokines (such as IL-1β) mediated by Cyr61 in macrophage derived from AOSD patients, thereby supplying evidence that Cyr61 is involved in the development of AOSD. Thus targeting Cyr61 may represent a potent strategy in psoriasis treatment.

成人斯蒂尔病（AOSD）是一种复杂的自身炎症性疾病。其发病机制尚不明确，一般认为与巨噬细胞过度活化并表达炎症因子（如IL-1β、IL-18及TNF-α等）所介导的炎症密切相关。富含半胱氨酸蛋白61（Cyr61）是一种分泌型基质蛋白，不仅在胚胎发育、血管生成、组织损伤修复及肿瘤发生中有重要作用，且被发现作为促炎症因子参与自身免疫病及炎症性疾病的发生。但是，Cyr61是否在AOSD中异常表达尚无报道。我们前期研究发现Cyr61在AOSD患者血浆中表达显著升高，鉴于Cyr61可促进炎症因子IL-1β、IL-6及TNF-α表达，推测Cyr61可能通过影响炎症微环境而参与AOSD发病。因此，本项目旨在通过培养AOSD患者外周血诱导的巨噬细胞来探索Cyr61介导巨噬细胞表达炎症因子（如IL-1β）及其信号通路，提出Cyr61参与AOSD发病新机制，将对深入了解AOSD发病机制、寻找新靶点提供有力证据。

本项目系统研究了Cyr61这一基质蛋白在成人斯蒂尔病（AOSD）不同亚型中的表达格局及其与临床表现和实验室检查的相关性。相比于健康对照（HC）和活动期AOSD (active AOSD)患者，Cyr61在稳定期的AOSD（inactive AOSD）患者血清中的表达是升高的，且Cyr61表达与AOSD系统性评分呈显著负相关，提示Cyr61跟疾病的缓解相关。同时，我们还发现，Cyr61表达与白细胞和中性粒细胞百分比呈现负相关；血清Cyr61表达在没有发热、一过性皮疹、咽痛、关节痛、淋巴结肿大的患者中显著高于具有这些临床表现的患者；Cyr61与IL-1β、IL-6及IL-17具有显著的负相关。有趣的是，Cyr61在关节炎型AOSD患者血清中表达升高，且与炎症因子呈现正相关。既往研究表明，Cyr61在不同病理状态下表现出促炎和抑炎的不同功能，因此，我们提出了Cyr61在AOSD中的双重作用：对系统型AOSD，Cyr61可作为疾病缓解的标志物，而对于关节炎型AOSD，Cyr61可作为疾病活动和炎症的标志物，并可能通过上调炎症因子表达参与炎症的放大过程。Cyr61在系统型（炎症但无显著局部病灶）和关节炎型（慢性炎症）中分别起到组织损伤和参与炎症损伤的截然相反的双重作用这一现象使我们对AOSD疾病不同临床分型的特征有了更加深入的了解，类似的作用机制在自身炎症性疾病发生发展中的作用需要更加深入的进行探讨。