Department of Biomedicine, Gastroenterology, University of Basel, Basel, Switzerland.
Department of Biomedicine, Hepatology, University of Basel, Basel, Switzerland.
Gut. 2023 May;72(5):821-833. doi: 10.1136/gutjnl-2022-327166. Epub 2022 May 25.
Disruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown.
Combining transcriptomic, proteomic and functional analyses, we studied the importance of the IL-20 subfamily for EoE using patient-derived oesophageal three-dimensional models and an EoE mouse model.
Patients with active EoE have increased expression of IL-20 subfamily cytokines in the oesophagus and serum. In patient-derived oesophageal organoids stimulated with IL-20 cytokines, RNA sequencing and mass spectrometry revealed a downregulation of genes and proteins forming the cornified envelope, including filaggrins. On the contrary, abrogation of IL-20 subfamily signalling in animals resulted in attenuated experimental EoE reflected by reduced eosinophil infiltration, lower Th2 cytokine expression and preserved expression of filaggrins in the oesophagus. Mechanistically, these observations were mediated by the mitogen-activated protein kinase (MAPK); extracellular-signal regulated kinases (ERK)1/2) pathway. Its blockade prevented epithelial barrier impairment in patient-derived air-liquid interface cultures stimulated with IL-20 cytokines and attenuated experimental EoE in mice.
Our findings reveal a previously unknown regulatory role of the IL-20 subfamily for oesophageal barrier function in the context of EoE. We propose that aberrant IL-20 subfamily signalling disturbs the oesophageal epithelial barrier integrity and promotes EoE development. Our study suggests that specific targeting of the IL-20 subfamily signalling pathway may present a novel strategy for the treatment of EoE.
上皮屏障的破坏在嗜酸性粒细胞性食管炎（EoE）的发展中起着至关重要的作用，EoE 是一种由 2 型辅助 T 细胞（Th2）介导的食物相关和变应原相关的慢性炎症性疾病。虽然已经报道了 Th2 介导的疾病中白细胞介素（IL）-20 亚家族成员（IL-19、IL-20 和 IL-24）的表达增加，但它们在 EoE 中的功能仍然未知。
通过结合转录组学、蛋白质组学和功能分析，我们使用患者来源的食管三维模型和 EoE 小鼠模型研究了 IL-20 亚家族对 EoE 的重要性。
患有活动性 EoE 的患者在食管和血清中表达增加的 IL-20 亚家族细胞因子。在 IL-20 细胞因子刺激的患者来源的食管类器官中，RNA 测序和质谱分析显示形成角蛋白包膜的基因和蛋白质下调，包括丝聚合蛋白。相反，在动物中阻断 IL-20 亚家族信号导致实验性 EoE 减轻，表现为嗜酸性粒细胞浸润减少、Th2 细胞因子表达降低和食管中丝聚合蛋白表达保留。在机制上，这些观察结果是由丝裂原活化蛋白激酶（MAPK）介导的；细胞外信号调节激酶（ERK）1/2）途径。其阻断可防止 IL-20 细胞因子刺激的患者来源的气液界面培养物中的上皮屏障损伤，并减轻小鼠中的实验性 EoE。
我们的研究结果揭示了 IL-20 亚家族在 EoE 背景下对食管屏障功能的未知调节作用。我们提出，异常的 IL-20 亚家族信号扰乱了食管上皮屏障的完整性，并促进了 EoE 的发展。我们的研究表明，针对 IL-20 亚家族信号通路的特异性靶向可能为 EoE 的治疗提供一种新策略。
