DR3 Regulates Intestinal Epithelial Homeostasis and Regeneration After Intestinal Barrier InjurySummary

Yosuke Shimodaira; Shyam K. More; Hussein Hamade; Anna Y. Blackwood; Jay P. Abraham; Lisa S. Thomas; Jordan H. Miller; Dalton T. Stamps; Sofi L. Castanon; Noam Jacob; Connie W.Y. Ha; Suzanne Devkota; David Q. Shih; Stephan R. Targan; Kathrin S. Michelsen

Cellular and Molecular Gastroenterology and Hepatology (Jan 2023)

DR3 Regulates Intestinal Epithelial Homeostasis and Regeneration After Intestinal Barrier InjurySummary

Yosuke Shimodaira,
Shyam K. More,
Hussein Hamade,
Anna Y. Blackwood,
Jay P. Abraham,
Lisa S. Thomas,
Jordan H. Miller,
Dalton T. Stamps,
Sofi L. Castanon,
Noam Jacob,
Connie W.Y. Ha,
Suzanne Devkota,
David Q. Shih,
Stephan R. Targan,
Kathrin S. Michelsen

Affiliations

Yosuke Shimodaira: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Shyam K. More: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Hussein Hamade: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Anna Y. Blackwood: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Jay P. Abraham: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Lisa S. Thomas: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Jordan H. Miller: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Dalton T. Stamps: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Sofi L. Castanon: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Noam Jacob: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
Connie W.Y. Ha: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Suzanne Devkota: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
David Q. Shih: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Stephan R. Targan: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
Kathrin S. Michelsen: F. Widjaja Foundation Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Correspondence Address correspondence to: Kathrin S. Michelsen, PhD, F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Davis Research Building, Room 4012, 110 George Burns Road, Los Angeles, California 90048.

Journal volume & issue: Vol. 16, no. 1
pp. 83 – 105

Abstract

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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: Clinical phenotype and histologic inflammation were assessed in C57BL/6 (wild-type), 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 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: Dr3-/- mice developed more severe colonic inflammation than wild-type mice in DSS-induced colitis with significantly impaired IEC regeneration. Homeostatic proliferation of IECs was increased in Dr3-/- mice, but blunted during regeneration. Cellular localization and expression of the tight junction proteins Claudin-1 and zonula occludens-1 were 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 conditions and impaired tissue repair and increased bacterial translocation during DSS-induced colitis. Impaired regenerative potential and altered zonula occludens-1 localization also were observed in Dr3ΔIEC 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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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