Protease-activated Receptor 2 Promotes Crohn's Disease-Associated Colonic Fibrosis through Fibroblast Activation

Area of Science:

• Gastroenterology
• Immunology
• Fibrosis Research

Background:

• Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor activated by serine proteases.
• PAR-2 activation promotes inflammatory and pro-fibrotic pathways by upregulating extracellular matrix (ECM) proteins and inflammatory cytokines.
• The role of PAR-2 in colonic fibrosis (CF), particularly in Crohn's disease, remains largely uninvestigated despite its high expression in the digestive system.

Purpose of the Study:

• To investigate the role of PAR-2 in Crohn's disease-associated colonic fibrosis.
• To elucidate the potential regulatory mechanisms of PAR-2 in this context.

Main Methods:

• Assessed PAR-2 expression in human and murine colon samples.
• Utilized immunofluorescence assays to analyze fibroblast phenotypic changes post-PAR-2 activation in the lamina propria.
• Conducted in vitro studies using CCD-18Co fibroblasts treated with a PAR-2 inhibitor (ENMD-1068) and agonist (SLIGRL-NH2).

Main Results:

• Elevated PAR-2 expression was observed in the subepithelial layer of colonic crypts in Crohn's disease patients and a murine fibrosis model, correlating with collagen deposition.
• Reducing PAR-2 in experimental colon fibrosis led to decreased collagen levels, reduced histological fibrosis, and attenuated colonic fibroblast activation.
• PAR-2 activation in vitro induced a profibrogenic phenotype and increased collagen synthesis in human colonic fibroblasts.

Conclusions:

• PAR-2 activation upregulates extracellular matrix (ECM) proteomic levels.
• PAR-2 activation promotes colonic fibrosis (CF).
• PAR-2 activation induces a pro-fibrogenic phenotype in human colonic myofibroblasts, highlighting its critical role in the fibrotic process.