Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians Universität, Munich, Germany.
Institute of Immunology, University of Muenster, Muenster, Germany.
Pharmacol Ther. 2016 Nov;167:120-131. doi: 10.1016/j.pharmthera.2016.07.015. Epub 2016 Aug 1.
Neutrophils and monocytes belong to the first line of immune defence cells and are recruited to sites of inflammation during infection or sterile injury. Both cells contain huge amounts of the heterodimeric protein S100A8/A9 in their cytoplasm. S100A8/A9 belongs to the Ca binding S100 protein family and has recently gained a lot of interest as a critical alarmin modulating the inflammatory response after its release (extracellular S100A8/A9) from neutrophils and monocytes. Extracellular S100A8/A9 interacts with the pattern recognition receptors Toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation Endproducts (RAGE) promoting cell activation and recruitment. Besides its biological function, S100A8/A9 (also known as myeloid related protein 8/14, MRP8/14) was identified as interesting biomarker to monitor disease activity in chronic inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 has been tested successfully in pre-clinical imaging studies to localize sites of infection or sterile injury. Finally, recent evidence using small molecule inhibitors for S100A8/A9 also suggests that blocking S100A8/A9 activity exerts beneficial effects on disease activity in animal models of autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. This review will provide a comprehensive and detailed overview into the structure and biological function of S100A8/A9 and also will give an outlook in terms of diagnostic and therapeutic applications targeting S100A8/A9.
中性粒细胞和单核细胞属于第一道免疫防御细胞，在感染或无菌损伤时被募集到炎症部位。这两种细胞的细胞质中都含有大量的异二聚体蛋白 S100A8/A9。S100A8/A9 属于 Ca 结合 S100 蛋白家族，最近因其从中性粒细胞和单核细胞中释放（细胞外 S100A8/A9）而作为关键警报素调节炎症反应而引起了广泛关注。细胞外 S100A8/A9 与模式识别受体 Toll 样受体 4（TLR4）和晚期糖基化终产物受体（RAGE）相互作用，促进细胞激活和募集。除了其生物学功能外，S100A8/A9（也称为髓样相关蛋白 8/14，MRP8/14）被确定为监测慢性炎症性疾病（包括炎症性肠病和类风湿关节炎）疾病活动的有趣生物标志物。此外，S100A8/A9 已在临床前成像研究中成功测试，以定位感染或无菌损伤部位。最后，最近使用 S100A8/A9 的小分子抑制剂的证据也表明，阻断 S100A8/A9 活性对包括多发性硬化症、系统性红斑狼疮、类风湿关节炎和炎症性肠病在内的自身免疫性疾病动物模型中的疾病活动具有有益作用。这篇综述将全面详细地介绍 S100A8/A9 的结构和生物学功能，并展望针对 S100A8/A9 的诊断和治疗应用。
