Drexler Stefan K, Kong Philip, Inglis Julia, Williams Richard O, Garlanda Cecilia, Mantovani Alberto, Yazdi Amir S, Brennan Fionula, Feldmann Marc, Foxwell Brian M J
Imperial College London, London, UK.
Arthritis Rheum. 2010 Aug;62(8):2249-61. doi: 10.1002/art.27517.
Single-immunoglobulin interleukin-1 receptor-related (SIGIRR), which is also known as Toll/interleukin-1 receptor 8 (TIR-8), is a member of the TIR domain-containing family of receptors and was first characterized as an inhibitor of interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling. In the Dextran sulfate sodium-induced colitis model, SIGIRR(-/-) mice were shown to have increased inflammation and to be more susceptible to endotoxin challenge. Increasing evidence implicates TLR and IL-1R signaling in the pathology of rheumatoid arthritis (RA). Therefore, the purpose of this study was to investigate the involvement of SIGIRR in regulating inflammation in disease-relevant models.
Primary human monocyte-derived macrophages and dendritic cells (DCs) were used to overexpress SIGIRR as well as to knock down endogenously expressed SIGIRR using small interfering RNAs. SIGIRR was also overexpressed in synovial cells derived from RA patients. To investigate the role of SIGIRR in vivo, zymosan-induced arthritis (ZIA) and collagen antibody-induced arthritis (CAIA) were induced in SIGIRR-knockout mice.
SIGIRR overexpression inhibited TLR-induced cytokine production in macrophages and DCs, while SIGIRR knockdown resulted in increased cytokine production following TLR stimulation. Moreover, SIGIRR overexpression inhibited the spontaneous release of cytokines by human RA synovial cells. The role of SIGIRR as an inhibitor of inflammation was confirmed in vivo, since SIGIRR(-/-) mice developed a more severe disease in both the ZIA and CAIA models.
Our study is the first to show the expression pattern and function of SIGIRR in primary human cells. Furthermore, this investigation defines the role of SIGIRR in disease-relevant cell types and demonstrates that SIGIRR is a potential therapeutic target for RA.
单免疫球蛋白白细胞介素-1受体相关分子（SIGIRR），也被称为Toll/白细胞介素-1受体8（TIR-8），是含TIR结构域受体家族的成员，最初被鉴定为白细胞介素-1受体（IL-1R）和Toll样受体（TLR）信号通路的抑制剂。在葡聚糖硫酸钠诱导的结肠炎模型中，SIGIRR基因敲除（SIGIRR(-/-)）小鼠表现出炎症加剧，且对内毒素攻击更敏感。越来越多的证据表明TLR和IL-1R信号通路与类风湿关节炎（RA）的发病机制有关。因此，本研究旨在探讨SIGIRR在疾病相关模型中调节炎症的作用。
使用原代人单核细胞来源的巨噬细胞和树突状细胞（DCs）过表达SIGIRR，并使用小干扰RNA敲低内源性表达的SIGIRR。SIGIRR也在RA患者来源的滑膜细胞中过表达。为了研究SIGIRR在体内的作用，在SIGIRR基因敲除小鼠中诱导酵母聚糖诱导的关节炎（ZIA）和胶原抗体诱导的关节炎（CAIA）。
SIGIRR过表达抑制巨噬细胞和DCs中TLR诱导的细胞因子产生，而SIGIRR敲低导致TLR刺激后细胞因子产生增加。此外，SIGIRR过表达抑制人RA滑膜细胞自发释放细胞因子。SIGIRR作为炎症抑制剂的作用在体内得到证实，因为SIGIRR(-/-)小鼠在ZIA和CAIA模型中病情更严重。
我们的研究首次展示了SIGIRR在原代人细胞中的表达模式和功能。此外，本研究确定了SIGIRR在疾病相关细胞类型中的作用，并证明SIGIRR是RA的潜在治疗靶点。
