POSTEC-CATHOLIC Biomedical Engineering Institute, The Catholic University of Korea, Seoul, South Korea.
Division of Rheumatology, Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, South Korea.
Front Immunol. 2020 Mar 10;11:195. doi: 10.3389/fimmu.2020.00195. eCollection 2020.
Calcium (Ca) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca store and then activates store-operated Ca entry (SOCE) to raise the intracellular Ca concentration, which is mediated by the Ca release-activated Ca (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca-calcineurin-NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.
钙（Ca）是一种重要的信号分子，控制着广泛的生物学功能。在免疫系统中，钙信号在多种细胞功能中起着核心作用，如增殖、分化、凋亡和许多基因转录。在免疫反应中，T 细胞和 B 细胞抗原受体的结合导致细胞内钙储存减少，然后激活钙储存操作钙内流（SOCE）以提高细胞内钙浓度，这是由钙释放激活钙（CRAC）通道介导的。最近，CRAC 通道的两个关键调节因子基质相互作用分子（STIM）和 Orai1 的鉴定，拓宽了我们对淋巴细胞钙信号调节机制的理解。细胞内钙的反复或持续增加是钙调神经磷酸酶介导的激活 T 细胞核因子（NFAT）去磷酸化所必需的。最近的数据表明，钙调神经磷酸酶-NFAT1 至 4 途径在自身免疫性疾病中失调。因此，钙调神经磷酸酶抑制剂环孢素和他克莫司已被用于治疗系统性红斑狼疮和类风湿关节炎等自身免疫性疾病。在这里，我们回顾了钙调神经磷酸酶-NFAT 信号通路在健康和疾病中的作用，重点讨论了 STIM 和 Orai1，并讨论了自身免疫性疾病中钙调节钙调神经磷酸酶-NFAT 途径的失调。
