Cathepsin S Is Activated During Colitis and Causes Visceral Hyperalgesia by a PAR2-Dependent Mechanism in Mice
Open accessAbstract
Background & aims Although proteases control inflammation and pain, the identity, cellular origin, mechanism of action, and causative role of proteases that are activated during disease are not defined. We investigated the activation and function of cysteine cathepsins (Cat) in colitis.Methods Because protease activity, rather than expression, is regulated, we treated mice with fluorescent activity-based probes that covalently modify activated cathepsins. Activated proteases were localized by tomographic imaging of intact mice and confocal imaging of tissues, and were identified by electrophoresis and immunoprecipitation. We examined the effects of activated cathepsins on excitability of colonic nociceptors and on colonic pain, and determined their role in colonic inflammatory pain by gene deletion.Results Tomography and magnetic resonance imaging localized activated cathepsins to the inflamed colon of piroxicam-treated il10(-/-) mice. Confocal imaging detected activated cathepsins in colonic macrophages and spinal neurons and microglial cells of mice with colitis. Gel electrophoresis and immunoprecipitation identified activated Cat-B, Cat-L, and Cat-S in colon and spinal cord, and Cat-S was preferentially secreted into the colonic lumen. Intraluminal Cat-S amplified visceromotor responses to colorectal distension and induced hyperexcitability of colonic nociceptors, which required expression of protease-activated receptor-2. Cat-S deletion attenuated colonic inflammatory pain induced with trinitrobenzene sulfonic acid.Conclusions Activity-based probes enable noninvasive detection, cellular localization, and proteomic identification of proteases activated during colitis and are potential diagnostic tools for detection of predictive disease biomarkers. Macrophage cathepsins are activated during colitis, and Cat-S activates nociceptors to induce visceral pain via protease-activated receptor-2. Cat-S mediates colitis pain and is a potential therapeutic target.
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Evidence from models of colitis indicates that PAR-2 activation contributes to nociceptor hyperexcitability.
“There is also evidence from models of colitis that PAR-2 activation contributes to nociceptor hyperexcitability.156”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [156]
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- Authors
- Cattaruzza, F., Lyo, V., Jones, E., Pham, D., Hawkins, J., Kirkwood, K., Valdez–Morales, E., Ibeakanma, C., Vanner, S. J., Bogyo, M., & Bunnett, N. W.
- Affiliations
- University of California, San Francisco (US)
- Queen's University (CA)
- Stanford Medicine (US)
- Monash University (AU)
- Corresponding author
- Bunnett, Nigel W.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 141
- Issue
- 5
- Pages
- 1864-1874.e3
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4041343
- OpenAlex
- W1972225809
- Cited by
- 103
- References
- 29
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 5 · 2023: 5 · 2022: 13 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 9 · 2013: 9 · 2012: 3
- FWCI
- 4.80
- 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)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-39957, R37DK039957, DK 43207, R01DK043207, DK57850, R01DK046285, R01DK039957, R56DK043207)
- National Institute of Biomedical Imaging and Bioengineering (R01EB005011, EB005011)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- cathepsin S, colitis, visceral hypersensitivity, protease-activated receptor 2, activity-based probes, macrophages, inflammatory pain, trinitrobenzene sulfonic acid, colonic distension, cathepsin B, cathepsin L, activity-based proteomics, disease biomarkers
- MeSH terms
- Animals, Cathepsin B, Cathepsins, Colitis, Colon, Crohn Disease, Disease Models, Animal, Hyperalgesia, Macrophages, Magnetic Resonance Imaging, Mice, Inbred C57BL, Nociceptors, Piroxicam, Signal Transduction, Interleukin-10, Gene Deletion, Mice, Knockout, Receptor, PAR-2, Mice, Cathepsin L, Visceral Pain
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