STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis.

Lokman Pang,Mariah G Alorro,Jennifer Huynh,Matthias Ernst,Xia Li,Ashwini L Chand

doi:10.3390/biomedicines9020187

Abstract

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

Highlights

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterised by chronic and relapsing inflammation of the gastrointestinal tract [1]
Our study indicates that IL-6ST/gp130/Signal Transducer and Activator of Transcription-3 (STAT3) signalling is critical in promoting intestinal barrier function and epithelial regeneration during colitis
Two mouse models were utilised to examine the significance of IL-6ST/gp130-dependent activation of STAT3 in intestinal barrier function during colitis

Summary

Introduction

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterised by chronic and relapsing inflammation of the gastrointestinal tract [1]. Intestinal epithelial cells (IECs) build a physical and biochemical barrier that segregates the intestinal microbiota and the underlying mucosal immune system to maintain homeostasis. Disruption of this barrier leads to increased intestinal permeability and allows the invasion of pathogenic microorganisms. Barrier dysfunction is associated with inflammation and a variety of diseases, including IBD and cancer [4]. It remains controversial whether dysfunction in the intestinal epithelial barrier acts as the initial driver for IBD or is of consequence to chronic inflammation

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Conclusion