IL-4 Receptor-Alpha Signalling of Intestinal Epithelial Cells, Smooth Muscle Cells, and Macrophages Plays a Redundant Role in Oxazolone Colitis.

Jennifer Claire Hoving,Maxine A Höft,Mumin Ozturk,Patricia Otieno-Odhiambo,Roanne Keeton,Frank Brombacher

doi:10.1155/2020/4361043

Abstract

A hallmark of ulcerative colitis is the chronic colonic inflammation, which is the result of a dysregulated intestinal mucosal immune response. Epithelial barrier disruption which allows the entry of microorganisms eventually leads to more aggressive inflammation and potentially the removal of the colon. We have previously shown that the T helper- (Th-) type 2 cytokines, Interleukin- (IL-) 4 and IL-13, mediate CD4+ T cell- or B cell-driven inflammation in the oxazolone-induced mouse model of ulcerative colitis. In contrast, mice deficient in the shared receptor of IL-4 and IL-13, IL-4 receptor-alpha (IL-4Rα), on all cells develop an exacerbated disease phenotype. This suggests that a regulatory role of IL-4Rα is required to protect against severe colitis. However, the cell populations responsible for regulating the severity of disease onset through IL-4Rα in colitis are yet to be identified. By deleting IL-4Rα on specific cell subsets shown to play a role in mediating colitis, we determined their role in a loss of function approach. Our data demonstrated that the loss of IL-4Rα signalling on intestinal epithelial cells, smooth muscle cells, and macrophages/neutrophils had no effect on alleviating the pathology associated with colitis. These results suggest that IL-4/IL-13 signalling through IL-4Rα on nonhematopoietic intestinal epithelial or smooth muscle cells and hematopoietic macrophage/neutrophils has a redundant role in driving acute oxazolone colitis.

Highlights

Intricate regulatory mechanisms in the intestine maintain homeostasis with the dysregulation of this balance often resulting in devastating inflammatory bowel disease
We concluded that CD4+ T helper- (Th-) type 2 cells producing IL-13 and B cells producing IgE were responsible for mediating colitis in mice [2]
While very mild inflammation and transient weight loss were induced in ethanol-only control mice, the disease parameters were significantly enhanced in oxazolone-treated mice

Summary

Introduction

Intricate regulatory mechanisms in the intestine maintain homeostasis with the dysregulation of this balance often resulting in devastating inflammatory bowel disease. In the oxazolone-induced colitis mouse model, Interleukin- (IL-) 13 is the main cytokine responsible for the pathology seen [1]. Based on both animal and patient data, the proposed mechanism for UC is that antigen is presented to and taken up by lamina propria antigen-presenting cells (APCs) including dendritic cells or macrophages. While IL-4/IL-13 signalling on both T cells and B cells contributes to the disease phenotype, our previous work showed that IL-4Rα deletion on all cell types significantly exacerbated disease compared to wild-type mice [7] This suggests the role of a yet to be identified cell type in preventing disease through IL-4Rα signalling. In an attempt to identify the responsible IL-4Rαexpressing cell type, we expanded our studies to include other cells known to be involved in colitis, including intestinal epithelial cells, smooth muscle cells, and macrophages

Methods

Results

Conclusion