DR3 Regulates Intestinal Epithelial Homeostasis and Regeneration After Intestinal Barrier Injury
Yosuke Shimodaira, Shyam K. More, Hussein Hamade, Anna Y. Blackwood, Jay P. Abraham, Lisa Thomas, Jordan H Miller, Dalton T. Stamps, Sofi Castanon, Noam Jacob, Connie Ha, Suzanne Devkota, David Q. Shih, Stephan R. Targan, Kathrin S. Michelsen
Abstract
BACKGROUND & AIMS: Tumor necrosis factor (TNF) superfamily member tumor necrosis factor-like protein 1A (TL1A) has been associated with the susceptibility and severity of inflammatory bowel diseases. However, the function of the tumor necrosis factor-like protein 1A and its receptor death receptor 3 (DR3) in the development of intestinal inflammation is incompletely understood. We investigated the role of DR3 expressed by intestinal epithelial cells (IECs) during intestinal homeostasis, tissue injury, and regeneration. METHODS: ) and assessed intestinal inflammation and epithelial barrier repair. In vivo intestinal permeability was assessed by fluorescein isothiocyanate dextran uptake. Proliferation of IECs was analyzed by bromodeoxyuridine incorporation. Expression of DR3 messenger RNA was assessed by fluorescent in situ hybridization. Small intestinal organoids were used to determine ex vivo regenerative potential. RESULTS: enteroids. CONCLUSIONS: Our findings establish a novel function of DR3 in IEC homeostasis and postinjury regeneration independent of its established role in innate lymphoid cells and T-helper cells.