Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation

Jean-Paul Motta,Céline Deraison,Emmanuel Mas,Derek M Mckay,Laurent Alric,Ana-Carolina Florence,David Sagnat,Anissa Edir,Muriel Quaranta-Nicaise,Nathalie Vergnolle,Corinne Rolland,Elena F Verdu,Perrine Rousset,Etienne Buscail,Delphine Bonnet,Chrystelle Bonnart,Laura Guiraud

doi:10.1038/s41385-021-00375-w

Abstract

Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.

Highlights

Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing-remitting gut conditions, with an increasing worldwide incidence.[1]
Elastase activity is detected in human intestinal epithelial cells (IEC) We investigated the cellular source of elastolytic activity in human colons from IBD patients and controls, using in situ zymography
In colonic tissue from IBD patients (CD patient shown in Fig. 1a), elastolytic activity was higher than what was detected in tissues from healthy

Summary

Introduction

Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing-remitting gut conditions, with an increasing worldwide incidence.[1] the precise aetiology of IBD is still unknown, it involves a complex interaction between genetic, environmental, microbial factors, and immune responses.[2] While most current treatments efficiently target the immune component of the disease, recent additional approaches focus on restoring tissue architecture and functions.[3,4,5,6] The goal of such new approaches is to delay and possibly avoid new flares, in an attempt to restore tissue homoeostasis. Epithelial functions might be severely flawed by such elastolytic overload. Aims of the present study were to identify the elastolytic protease(s) expressed and active in tissues from IBD patients and to understand the role of such elastolytic activity in epithelial cell biology

Methods

Results

Conclusion