Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-05-04 , DOI: 10.1016/j.jcmgh.2020.04.014 Kevin A Bockerstett 1 , Christine P Petersen 2 , Christine N Noto 1 , Lindsey M Kuehm 1 , Chun Fung Wong 1 , Eric L Ford 1 , Ryan M Teague 1 , Jason C Mills 3 , James R Goldenring 2 , Richard J DiPaolo 1
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Background & Aims
The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis.
Methods
We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues.
Results
We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes.
Conclusions
In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell–mediated inflammation in the gastric mucosa.
中文翻译：
白细胞介素 27 可防止慢性自身免疫性胃炎期间的胃萎缩和化生。
背景与目标
慢性炎症与胃癌发生之间的关联已得到充分证实，但尚不清楚免疫细胞和细胞因子如何调节这一过程。我们研究了白细胞介素 27 (IL27) 在患有自身免疫性胃炎的小鼠胃萎缩、增生和化生（与炎症诱发的胃癌相关的癌前病变）发展中的作用。
方法
我们对 TxA23 小鼠（对照小鼠）和 TxA23x Ebi3 -/- 小鼠进行了研究，TxA23 小鼠表达针对 H+/K+ 三磷酸腺苷酶 α 链的 T 细胞受体，并发展为自身免疫性胃炎，而 TxA23x Ebi3 -/-小鼠则发展为胃炎，但不表达 IL27。在一些实验中，小鼠被给予高剂量他莫昔芬以诱导壁细胞萎缩和解痉多肽表达化生（SPEM）。使用微型渗透泵将重组 IL27 给予小鼠。收集胃并通过组织病理学和免疫荧光进行分析；我们使用流式细胞术测量IL27并鉴定胃粘膜中分泌IL27的免疫细胞。对浸润胃组织的免疫细胞进行了单细胞 RNA 测序。
结果
我们在慢性胃炎小鼠（TxA23 小鼠）体内发现了分泌 IL27 的巨噬细胞和树突状细胞。缺乏 IL27 的小鼠比对照小鼠出现更严重的胃炎、萎缩和 SPEM。给予重组IL27可显着降低胃炎小鼠炎症、萎缩和SPEM的严重程度。单细胞 RNA 测序表明，IL27 几乎只作用于胃浸润 CD4+ T 细胞，抑制炎症基因的表达。
结论
在对患有自身免疫性胃炎的小鼠的研究中，我们发现 IL27 是胃炎和 SPEM 的抑制剂，可抑制 CD4+ T 细胞介导的胃粘膜炎症。
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