TNF超家族成员TL1A已与炎症性肠病的易感性和严重程度相关联。然而，TL1A及其受体DR3在肠道炎症发展中的作用尚不完全了解。我们研究了肠道上皮细胞（IEC）中表达的DR3在肠道稳态、组织损伤和再生过程中的作用。在诱导DSS结肠炎的C57BL/6（WT）、Tl1a-/-和Dr3-/-小鼠中评估了临床表型和组织学炎症。我们生成了具有IEC特异性DR3删除（Dr3ΔIEC）的小鼠，并评估了肠道炎症和上皮屏障修复。通过荧光异硫氰酸偶氮苯-葡聚糖摄取评估了体内肠道通透性。通过溴脱氧尿嘧啶的内含物分析了IEC的增殖。利用荧光原位杂交检测了DR3 mRNA的表达。利用小肠器官样品确定了体外再生潜能。Dr3-/-小鼠在DSS诱导的结肠炎中比WT小鼠更严重，且IEC再生明显受损。Dr3-/-小鼠的稳态增殖增加，但在再生过程中受到抑制。紧密连接蛋白Claudin-1和zonula occudens-1（ZO-1）的细胞定位和表达发生改变，导致稳态肠道通透性增加。Dr3ΔIEC小鼠重复观察到了Dr3-/-小鼠的表型，在稳态条件下增加了肠道通透性和IEC增殖，在DSS诱导的结肠炎期间出现了组织修复受损和细菌转位增加。在Dr3ΔIEC肠细胞瘤中，也观察到再生潜能受损和ZO-1定位改变。我们的研究结果建立了DR3在IEC稳态和受伤后再生中的新功能，独立于其在天然淋巴细胞和T辅助细胞中的已知作用。 版权所有 © 2023 The Authors. Elsevier Inc. 发布。保留所有权利。

TNF superfamily member TL1A has been associated with susceptibility and severity of inflammatory bowel diseases. However, the function of TL1A and its receptor DR3 in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IEC) during intestinal homeostasis, tissue injury, and regeneration.Clinical phenotype and histological inflammation were assessed in C57BL/6 (WT), Tl1a-/-, and Dr3-/- mice in dextran sulfate sodium (DSS)-induced colitis. We generated mice with an IEC-specific deletion of DR3 (Dr3ΔIEC) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by Fluorescein isothiocyanate dextran uptake. Proliferation of IEC was analyzed by Bromodeoxyuridine incorporation. Expression of DR3 mRNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential.Dr3-/- mice developed more severe colonic inflammation than WT mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IEC was increased in Dr3-/- mice but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occudens-1 (ZO-1) was altered leading to increased homeostatic intestinal permeability. Dr3ΔIEC mice recapitulated the phenotype observed in Dr3-/- mice with increased intestinal permeability and IEC proliferation under homeostatic condition and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered ZO-1 localization was also observed in Dr3ΔIEC enteroids.Our findings establish a novel function of DR3 in IEC homeostasis and post-injury regeneration independent of its established role in innate lymphoid cells and T helper cells.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.