Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Gastroenterol. 2020 May;55(5):565-576. doi: 10.1007/s00535-020-01662-2. Epub 2020 Jan 20.
Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified.
Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients.
IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP.
These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.
浆细胞样树突状细胞（pDCs）过度产生 I 型干扰素（IFN-I）可促进自身免疫。最近，我们报道称，实验性自身免疫性胰腺炎（AIP）和人类 1 型 AIP 的一个显著特征是 pDC 激活，随后 IFN-I 和 IL-33 的产生增强。然而，干扰素调节因子 7（IRF7）在这些疾病中的作用尚未阐明，IRF7 是 pDC 中 IFN-I 产生的关键转录因子。
从表现出 AIP 的 MRL/MpJ 小鼠的胰腺单核细胞（PMNC）中分离全细胞和核提取物。通过免疫印迹法检查这些提取物中磷酸化 IRF7 的表达和 IRF7 的核转位。通过免疫荧光分析评估实验性 AIP 中胰腺 IRF7 的表达。通过从 1 型 AIP 患者的外周血 pDC 中评估中性粒细胞胞外陷阱（NETs）暴露后 IRF7 的核转位。在 1 型 AIP 患者的手术标本中检查胰腺 IRF7 的表达。
在实验性 AIP 中，IRF7 在胰腺 pDC 中被激活。IRF7 表达的 siRNA 介导的敲低可防止 AIP 的发展，这伴随着胰腺 pDC 积聚和 IFN-α和 IL-33 产生的显著减少。值得注意的是，与来自健康对照的 pDC 相比，从 1 型 AIP 患者分离的外周血 pDC 中 IRF7 的核转位增强。此外，在 1 型 AIP 患者的胰腺中检测到表达 IRF7 的 pDC。
这些发现表明，pDC 中激活的 IRF7-IFN-I-IL-33 轴驱动与 1 型 AIP 相关的致病性固有免疫反应。
