Protease-Activated Receptor 2, Dipeptidyl Peptidase I, and Proteases Mediate Clostridium difficile Toxin A Enteritis
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Background & aims We studied the role of protease-activated receptor 2 (PAR(2)) and its activating enzymes, trypsins and tryptase, in Clostridium difficile toxin A (TxA)-induced enteritis.Methods We injected TxA into ileal loops in PAR(2) or dipeptidyl peptidase I (DPPI) knockout mice or in wild-type mice pretreated with tryptase inhibitors (FUT-175 or MPI-0442352) or soybean trypsin inhibitor. We examined the effect of TxA on expression and activity of PAR(2) and trypsin IV messenger RNA in the ileum and cultured colonocytes. We injected activating peptide (AP), trypsins, tryptase, and p23 in wild-type mice, some pretreated with the neurokinin 1 receptor antagonist SR140333.Results TxA increased fluid secretion, myeloperoxidase activity in fluid and tissue, and histologic damage. PAR(2) deletion decreased TxA-induced ileitis, reduced luminal fluid secretion by 20%, decreased tissue and fluid myeloperoxidase by 50%, and diminished epithelial damage, edema, and neutrophil infiltration. DPPI deletion reduced secretion by 20% and fluid myeloperoxidase by 55%. In wild-type mice, FUT-175 or MPI-0442352 inhibited secretion by 24%-28% and tissue and fluid myeloperoxidase by 31%-71%. Soybean trypsin inhibitor reduced secretion to background levels and tissue myeloperoxidase by up to 50%. TxA increased expression of PAR(2) and trypsin IV in enterocytes and colonocytes and caused a 2-fold increase in Ca(2+) responses to PAR(2) AP. AP, tryptase, and trypsin isozymes (trypsin I/II, trypsin IV, p23) caused ileitis. SR140333 prevented AP-induced ileitis.Conclusions PAR(2) and its activators are proinflammatory in TxA-induced enteritis. TxA stimulates existing PAR(2) and up-regulates PAR(2) and activating proteases, and PAR(2) causes inflammation by neurogenic mechanisms.
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Mucosal damage and inflammation caused by toxin A from C. difficile is markedly reduced when PAR-2 activation is prevented.
“Mucosal damage and inflammation caused by toxin A from the enteric pathogen C. difficile is markedly reduced when PAR-2 activation is prevented.135”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [135]
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- Authors
- Cottrell, G. S., Amadesi, S., Pikios, S., Camerer, E., Willardsen, J. A., Murphy, B. R., Caughey, G. H., Wolters, P. J., Coughlin, S. R., Peterson, A., Knecht, W., Pothoulakis, C., Bunnett, N. W., & Grady, E. F.
- Affiliations
- University of California, San Francisco (US)
- AstraZeneca (Sweden) (SE)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Grady, Eileen F.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 132
- Issue
- 7
- Pages
- 2422-2437
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC2366898
- OpenAlex
- W2058871622
- Cited by
- 56
- References
- 59
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 1 · 2016: 2 · 2014: 2 · 2013: 5 · 2012: 4
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Heart, Lung, and Blood Institute
- Crohn's and Colitis Foundation of America (DK57840, DK52388, DK47343, DK39957, HL024136, DK43207, DK41301, 1730)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Clostridium difficile and Clostridium perfringens research
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- protease-activated receptor 2, dipeptidyl peptidase I, Clostridium difficile toxin A, tryptase, p23, tryptase inhibitors, neurokinin-1 receptor, SR140333, ileitis, intestinal secretion, myeloperoxidase, neutrophil infiltration, neurogenic inflammation
- MeSH terms
- Animals, Bacterial Toxins, Cells, Cultured, Colon, Enteritis, Enterotoxins, Granulocytes, Ileitis, Ileum, Intestinal Mucosa, Intestines, Peroxidase, Nervous System, Peptide Hydrolases, Trypsin, Trypsin Inhibitors, Up-Regulation, Receptors, Neurokinin-1, Mice, Knockout, Cathepsin C, Receptor, PAR-2, Mice, Tryptases
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