2. Academic Validation
  3. Elafin Reverses Intestinal Fibrosis by Inhibiting Cathepsin S-Mediated Protease-Activated Receptor 2

Elafin Reverses Intestinal Fibrosis by Inhibiting Cathepsin S-Mediated Protease-Activated Receptor 2

  • Cell Mol Gastroenterol Hepatol. 2022;14(4):841-876. doi: 10.1016/j.jcmgh.2022.06.011.
Ying Xie 1,  Lindsey Fontenot 2,  Andrea Chupina Estrada 2,  Becca Nelson 2,  Jiani Wang 1,  David Q Shih 3,  Wendy Ho 2,  S Anjani Mattai 4,  Florian Rieder 5,  Dane D Jensen 6,  Nigel W Bunnett 7,  Hon Wai Koon 8
Affiliations

Affiliations

  • 1 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Department of Gastroenterology, The First Hospital of China Medical University, Shenyang City, Liaoning Province, China.
  • 2 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
  • 3 F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
  • 4 Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
  • 5 Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
  • 6 Bluestone Center for Clinical Research, New York University College of Dentistry, New York, New York.
  • 7 Department of Molecular Pathobiology, Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, New York.
  • 8 Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California. Electronic address: hkoon@mednet.ucla.edu.
PMID: 35840034 DOI: 10.1016/j.jcmgh.2022.06.011
Abstract

Background & aims: More than half of Crohn's disease patients develop intestinal fibrosis-induced intestinal strictures. Elafin is a human Protease inhibitor that is down-regulated in the stricturing intestine of Crohn's disease patients. We investigated the efficacy of elafin in reversing intestinal fibrosis and elucidated its mechanism of action.

Methods: We developed a new method to mimic a stricturing Crohn's disease environment and induce fibrogenesis using stricturing Crohn's disease patient-derived serum exosomes to condition fresh human intestinal tissues and primary stricturing Crohn's disease patient-derived intestinal fibroblasts. Three mouse models of intestinal fibrosis, including SAMP1/YitFc mice, Salmonella-infected mice, and trinitrobenzene sulfonic acid-treated mice, were also studied. Elafin-Eudragit FS30D formulation and elafin-overexpressing construct and lentivirus were used.

Results: Elafin reversed collagen synthesis in human intestinal tissues and fibroblasts pretreated with Crohn's disease patient-derived serum exosomes. Proteome arrays identified Cathepsin S as a novel fibroblast-derived pro-fibrogenic Protease. Elafin directly suppressed Cathepsin S activity to inhibit Protease-activated Receptor 2 activity and Zinc finger E-box-binding homeobox 1 expression, leading to reduced collagen expression in intestinal fibroblasts. Elafin overexpression reversed ileal fibrosis in SAMP1/YitFc mice, cecal fibrosis in Salmonella-infected mice, and colonic fibrosis in trinitrobenzene sulfonic acid-treated mice. Cathepsin S, Protease-activated Receptor 2 agonist, and zinc finger E-box-binding homeobox 1 overexpression abolished the anti-fibrogenic effect of elafin in fibroblasts and all 3 mouse models of intestinal fibrosis. Oral elafin-Eudragit FS30D treatment abolished colonic fibrosis in trinitrobenzene sulfonic acid-treated mice.

Conclusions: Elafin suppresses collagen synthesis in intestinal fibroblasts via Cathepsin S-dependent Protease-activated Receptor 2 inhibition and decreases zinc finger E-box-binding homeobox 1 expression. The reduced collagen synthesis leads to the reversal of intestinal fibrosis. Thus, modified elafin may be a therapeutic approach for intestinal fibrosis.

Keywords

Fibrosis; Protease; Receptor.

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