Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Immunology. 2022 Jun;166(2):210-221. doi: 10.1111/imm.13468. Epub 2022 Mar 24.
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease. Increased incidence of T1D was reported in patients receiving IFN-α treatment. However, the exact mechanisms of IFN-α that facilitate the pathogenesis of T1D are not fully understood. To explore the mechanism of IFN-α on the immune system and islets, non-obese diabetic (NOD) mice were injected with IFN-α and the progression of autoimmune insulitis was assessed by haematoxylin and eosin (HE) staining, immunohistochemical and flow cytometry analysis. Transcriptional profiling of islets treated with IFN-α was explored by RNA-seq. IFN-α induced antigen presentation was evaluated by qRT-PCR, western blot and immunofluorescence, and key transcription factors were inhibited by small interfering RNAs (siRNAs). Our data show that IFN-α contributed to the progression of autoimmune insulitis in NOD mice by promoting the proliferation of CD8+ T cells. IFN-α upregulated antigen presentation related genes MHC I, TAP1, B2M, PSMB8, NLRC5 and transcriptional regulator STAT1, STAT2, IRF7 at a time and dose-dependent manner. The silence of STAT1 or STAT2 both weakened IFN-α-induced increase of antigen presenting related molecules. IRF7 was also merely influenced by STAT1 silence. The knockdown of IRF7 decreased the IFN-α induced expressions of TAP1, PSMB8 and MHC I and prevented the expression of STAT2 but not STAT1. Our study demonstrated that STAT1-IRF7-MHC I complex axis were crucial for IFN-α signalling in islets, and created positive feedback through IRF7-STAT2 cascade amplifying signals which accelerated the process of T1D.
1 型糖尿病（T1D）是一种 T 细胞介导的自身免疫性疾病。有报道称，接受 IFN-α 治疗的患者 T1D 的发病率增加。然而，IFN-α 促进 T1D 发病的确切机制尚不完全清楚。为了探讨 IFN-α 对免疫系统和胰岛的作用机制，用 IFN-α 注射非肥胖型糖尿病（NOD）小鼠，并通过苏木精和伊红（HE）染色、免疫组化和流式细胞术分析评估自身免疫性胰岛炎的进展。通过 RNA-seq 探索 IFN-α 处理的胰岛的转录谱。通过 qRT-PCR、western blot 和免疫荧光评估 IFN-α 诱导的抗原呈递，并通过小干扰 RNA（siRNA）抑制关键转录因子。我们的数据表明，IFN-α 通过促进 CD8+T 细胞的增殖促进 NOD 小鼠自身免疫性胰岛炎的进展。IFN-α 以时间和剂量依赖的方式上调抗原呈递相关基因 MHC I、TAP1、B2M、PSMB8、NLRC5 和转录调节因子 STAT1、STAT2、IRF7。STAT1 或 STAT2 的沉默均减弱了 IFN-α 诱导的抗原呈递相关分子的增加。IRF7 也仅受 STAT1 沉默的影响。IRF7 的敲低降低了 IFN-α 诱导的 TAP1、PSMB8 和 MHC I 的表达，并阻止了 STAT2 但不是 STAT1 的表达。我们的研究表明，STAT1-IRF7-MHC I 复合物轴在胰岛中是 IFN-α 信号的关键，并且通过 IRF7-STAT2 级联放大信号产生正反馈，加速了 T1D 的发生。
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