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

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.

Proteolytic Cleavage of Bioactive Peptides and Protease-Activated Receptors in Acute and Post-Colitis

“…First, we used pure proteases to determine the cleavage patterns of the peptides that were based on in vivo substrates. Different trypsin-like and elastase-like proteases, which have been proposed to be involved in IBS and IBD [ 2 , 3 , 4 , 8 , 9 , 10 , 12 , 13 , 14 , 15 , 16 ], cleaved the peptides with different efficiencies. Both VIP and β-endorphin could be used to differentiate between the studied proteases.…”

“…In addition to an increased trypsin-like activity, an increased elastase-like activity was measured in human colonic tissue and DSS or TNBS-induced colitis mice [ 10 , 15 ]. In situ zymography on colonic biopsies from IBD patients showed an increased elastase activity compared to colon from healthy individuals.…”

“…Elastase-2 is probably responsible for this increased activity since the level of this protein is also increased in colonic IBD tissues. Similarly, increased mRNA expression and an increased immunostaining for elastase-2 were observed in colonic tissue from DSS-induced colitis mice [ 15 ].…”

Antimicrobial peptides and the gut microbiome in inflammatory bowel disease

“…Elafin is known to be markedly upregulated in the intestinal mucosa of UC patients[ 130 , 131 ]. Intestinal expression seems to correlate closely with disease progression, as elevated concentrations are detectable in the right colon of patients with pan-colonic disease, but not those with exclusively left-sided disease[ 130 ]. This finding is further supported by enhanced colonic mRNA immunostaining in inflamed relative to non-inflamed UC samples[ 131 ].…”

Protease-Activated Receptors – Key Regulators of Inflammatory Bowel Diseases Progression

“…Accumulating evidence demonstrates that PAR 1 and PAR 2 are involved in the modulation of immune response in IBD. 13 , 29–32 , 36–41 Immunomodulatory action of PAR 1 in the colon was estimated by Cenac et al, who used specific peptides which act as PAR 1 agonists. 37 In an animal model of oxazolone-induced colitis, selective activation of PAR 1 reduced macroscopic colon damage score and myeloperoxidase activity as well as colon wall thickness in comparison to mice treated with oxazolone and control peptide.…”