Shigesaka Minoru, Ito Tomoki, Inaba Muneo, Imai Kai, Yamanaka Hideki, Azuma Yoshiko, Tanaka Akihiro, Amuro Hideki, Nishizawa Tohru, Son Yonsu, Satake Atsushi, Ozaki Yoshio, Nomura Shosaku
First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka, 573-1010, Japan.
Arthritis Res Ther. 2020 Nov 9;22(1):264. doi: 10.1186/s13075-020-02356-z.
Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs.
We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production.
We found that treatment with 1-10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs.
Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.
体液免疫和细胞免疫机制均参与系统性红斑狼疮（SLE）自身免疫反应的发生和发展。浆细胞样树突状细胞（pDC）通过I型干扰素（IFN）产生失调在SLE发病机制中起核心作用；这些细胞与活化的髓样树突状细胞（mDC）共同作用，放大自身免疫性疾病的恶性致病循环。因此，控制SLE中异常的树突状细胞激活可能为治疗该疾病提供一种替代策略。霉酚酸酯（MMF）已用于治疗狼疮性肾炎它通过抑制肌苷-5-单磷酸脱氢酶特异性阻断B和T淋巴细胞的增殖。在此，我们重点研究MMF对树突状细胞功能的影响，尤其是pDC的IFN反应。
我们通过流式细胞术分离人血pDC和mDC，并检测霉酚酸（MPA，MMF的代谢产物）对树突状细胞亚群的Toll样受体（TLR）配体反应的影响。此外，我们在有或无MPA的情况下用SLE患者的血清培养pDC，然后检测MPA对SLE血清诱导的IFN-α产生的抑制作用。
我们发现，用1-10 μM的MPA处理（涵盖临床血浆谷浓度范围），分别响应R848或CpG-ODN时，剂量依赖性下调mDC（而非pDC）上CD80和CD86的表达，且不诱导细胞凋亡。值得注意的是，在pDC中，MPA通过IRF7核转位显著抑制IFN-α产生，并抑制AKT活性。此外，MPA抑制mDC中IL-12的产生及STAT4的表达。我们进一步确定MPA对pDC的SLE血清诱导的IFN-α产生具有抑制作用。
我们的数据表明，MPA可通过调节树突状细胞亚群的功能中断自身免疫性疾病的恶性致病循环。这项工作揭示了MMF治疗SLE的新机制。
