Critical role of interferons in gastrointestinal injury repair

Constance Mcelrath,Mark Galan,Joan E Durbin,Heidi Risman,Sergey V Smirnov,Marvin J Sandoval,Hsiang-Chi Tseng,Raghavendra Sridhar,Amariliz Rivera,Raymond B Birge,Jianya Peng,Jian-Da Lin,Viralkumar Davra,Sergei V Kotenko,Yun-Juan Chang,Orchi Dutta,Brian P Pollack,Vanessa Espinosa

doi:10.1038/s41467-021-22928-0

Abstract

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.

Highlights

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators
As IFNs are pluripotent cytokines known to exert tumor-suppressive actions through a variety of mechanisms[22,23,24,25,26], we initially set out to evaluate the role of type I and type III IFNs in colon cancer development in the AOM/dextran sulfate sodium (DSS) model of inflammation-induced colorectal cancer (CRC)
Wild type (WT) and single type I or type III IFN receptor (IFNR)-deficient (Ifnar1−/− or Ifnlr1−/−) or double IFNR-deficient (Ifnar1−/−Ifnlr1−/−) mice were administered a single intraperitoneal (IP) injection of the carcinogen AOM followed by three cycles of 1.5% DSS in the drinking water for 7 days followed by regular water for 14 days (Supplementary Fig. 1a)

Summary

Introduction

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. The association of IBD with an increased incidence of colorectal cancer (CRC) highlights the dysregulated interaction between immune and epithelial cells at this barrier surface and the need to elucidate the underlying etiology of UC To this end, several mouse models have been generated to study inflammation-induced CRC and colitis. The robust and highly reproducible azoxymethane/ dextran sodium sulfate (AOM/DSS) model has been used to study inflammation-induced CRC and the DSS model to study acute colitis Studies using these models have identified several cytokines and growth factors important for promoting mucosal healing following DSS-induced injury, including IL-22 and IL-339–11.

Methods

Results

Conclusion