Department of Immunology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan.
Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan.
Int Immunol. 2022 Feb 23;34(3):159-172. doi: 10.1093/intimm/dxab103.
Type I IFNs (IFN-α and IFN-β), immunomodulatory cytokines secreted from activated plasmacytoid dendritic cells (pDCs), contribute to the innate defense against pathogenic infections and the pathogenesis of the autoimmune disease psoriasis vulgaris. A previous study has shown that an E26 transformation-specific (Ets) family transcription factor Spi-B can transactivate the type I IFN promoter in synergy with IFN regulatory factor (IRF)-7 and is required for type I IFN production in pDCs. However, the mechanism of negative regulation of type I IFNs by pDCs remains unknown. In this study, we report that a basic leucine zipper (bZip) transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MafB) suppresses the induction of type I IFNs in pDCs. The elevated expression of MafB inhibited the transactivation of type I IFN genes in a dose-dependent manner. At the molecular level, MafB interacted with the Ets domain of Spi-B and interfered with IRF-7-Spi-B complexation. Decreased MafB mRNA expression and degradation of MafB protein in the early phase of immune responses led to the enhancement of type I IFNs in pDCs. In vivo studies indicated that MafB is involved in resistance against imiquimod-induced psoriasis-like skin inflammation. Overall, these findings demonstrate that MafB acts as a negative regulator of type I IFN induction in pDCs and plays an important role in maintaining immune homeostasis.
I 型干扰素 (IFN-α 和 IFN-β) 是由活化的浆细胞样树突状细胞 (pDC) 分泌的免疫调节细胞因子，有助于先天防御病原体感染和寻常型银屑病等自身免疫性疾病的发病机制。先前的研究表明，E26 转化特异性 (Ets) 家族转录因子 Spi-B 可以与干扰素调节因子 (IRF)-7 协同转激活 I 型 IFN 启动子，并且是 pDC 中产生 I 型 IFN 所必需的。然而，pDC 下调 I 型 IFN 的机制尚不清楚。在这项研究中，我们报告了碱性亮氨酸拉链 (bZip) 转录因子 v-maf 肌肉腱膜纤维肉瘤癌基因同源物 B (MafB) 抑制 pDC 中 I 型 IFN 的诱导。MafB 的表达上调以剂量依赖的方式抑制 I 型 IFN 基因的转录激活。在分子水平上，MafB 与 Spi-B 的 Ets 结构域相互作用，并干扰了 IRF-7-Spi-B 复合物的形成。在免疫反应的早期阶段，MafB mRNA 表达降低和 MafB 蛋白降解导致 pDC 中 I 型 IFN 的增强。体内研究表明，MafB 参与了咪喹莫特诱导的银屑病样皮肤炎症的抵抗。总的来说，这些发现表明 MafB 作为 pDC 中 I 型 IFN 诱导的负调控因子发挥作用，并在维持免疫稳态中发挥重要作用。
