Background & Aims

Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP.

Methods

We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow–derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI).

Results

STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than mice given wild-type bone marrow. DNA from dying acinar cells activated STING signaling in macrophages, which was inhibited by addition of DNaseI.

Conclusions

In mice with AP, STING senses acinar cell death (by detecting DNA from dying acinar cells) and activates a signaling pathway that promotes inflammation. Macrophages express STING and activate pancreatic inflammation in AP.

中文翻译：

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STING信号促进实验性急性胰腺炎的炎症。

背景与目标

急性胰腺炎（AP）的特征在于严重的炎症和腺泡细胞死亡。跨膜蛋白173（TMEM173或STING）是免疫细胞上的DNA传感器衔接蛋白，可识别胞质核酸并传递激活干扰素产生和先天免疫应答的信号。我们调查了白细胞STING信号传导是否会介导AP小鼠的炎症。

方法

我们通过注射铜蓝蛋白或放置在缺乏胆碱的DL-乙硫氨酸饮食中诱导C57BL / 6J小鼠（对照）和C57BL / 6J-Tmem173gt / J小鼠（STING敲除小鼠）中的AP。在某些小鼠中，STING信号传导是通过施用药理激动剂诱导的。在对照或STING敲除小鼠的骨髓移植的C57BL / 6J小鼠中以及在环GMP-AMP合酶（Cgas）基因。收集胰腺，通过组织学分析，并通过流式细胞术，定量聚合酶链反应，免疫印迹和酶联免疫吸附测定法分离和分析痤疮。从小鼠中收集骨髓来源的巨噬细胞，并测试它们在存在和不存在脱氧核糖核酸酶（DNaseI）的情况下从垂死的腺泡细胞中检测DNA的能力。

结果

STING信号在患有AP的小鼠的胰腺中被激活，但是没有AP的小鼠未被激活。与对照组小鼠相比，STING基因敲除小鼠的AP严重程度较低（水肿，炎症和胰腺损伤标志物较少），而给予STING激动剂的小鼠的AP较对照组严重。在从胰腺收集的免疫细胞中，STING主要在巨噬细胞中表达。与不使用AP相比，有和没有AP的小鼠中cGAS的水平均升高，与对照组相比，cGAS敲除小鼠在诱发AP后具有减轻的水肿，炎症和其他胰腺损伤标志物。从STING基因敲除小鼠接受骨髓移植的野生型小鼠，与诱导后的AP相比，胰腺损伤更少，脂肪酶和胰腺胰蛋白酶的血清水平更低。

结论

在患有AP的小鼠中，STING可以检测腺泡细胞的死亡（通过检测垂死的腺泡细胞的DNA）并激活促进炎症的信号传导途径。巨噬细胞表达STING并激活AP中的胰腺炎症。