Objective The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. Design To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. Results As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. Conclusions Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. Trial registration number NCT02749630.

中文翻译：

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白细胞介素22在结肠上皮细胞中协调病理性内质网应激反应转录程序

目的白细胞介素22（IL22）在慢性炎症中的功能作用存在争议，并且缺乏对其如何调节靶组织的机制见解。在这项研究中，我们评估了 IL22 在慢性结肠炎中的功能作用，并探讨了 IL22 介导的结肠上皮细胞调节的机制。设计 为了研究 IL22 在慢性结肠炎中的功能作用以及它如何调节结肠上皮细胞，我们在人类 IBD 中采用了一个三维微型肠道上皮类器官系统、体内疾病模型和转录组数据集。结果 除了诱导与抗菌反应有关的转录模块外，IL22 还协调结肠上皮细胞中的内质网 (ER) 应激反应转录程序。在活动性结肠克罗恩病 (CD) 患者的结肠中，IL22反应性转录模块和ER应激反应模块富集。引人注目的是，在慢性结肠炎的 IL22 依赖性模型中，靶向 IL22 可减轻结肠上皮 ER 应激并减轻结肠炎。ER 应激反应的药理学调节同样影响结肠炎的严重程度。在结肠 CD 患者中，同时阻断 IL12 和 IL23（IL22 产生的关键上游调节因子）的抗体阻断 IL12p40 可减轻结肠上皮 ER 应激反应。结论 我们的数据挑战了 IL22 作为 IBD 中主要有益细胞因子的看法，并为 IL22 介导的慢性结肠炎致病性的分子机制提供了新的见解。靶向 IL22 调节通路和减轻结肠上皮 ER 应激可能代表结肠炎患者的有希望的治疗策略。试用注册号 NCT02749630。