Mast Cell Tryptase Controls Paracellular Permeability of the Intestine
Open accessAbstract
Tight junctions between intestinal epithelial cells prevent ingress of luminal macromolecules and bacteria and protect against inflammation and infection. During stress and inflammation, mast cells mediate increased mucosal permeability by unknown mechanisms. We hypothesized that mast cell tryptase cleaves protease-activated receptor 2 (PAR2) on colonocytes to increase paracellular permeability. Colonocytes expressed PAR2 mRNA and responded to PAR2 agonists with increased [Ca2+]i. Supernatant from degranulated mast cells increased [Ca2+]i in colonocytes, which was prevented by a tryptase inhibitor, and desensitized responses to PAR2 agonist, suggesting PAR2 cleavage. When applied to the basolateral surface of colonocytes, PAR2 agonists and mast cell supernatant decreased transepithelial resistance, increased transepithelial flux of macromolecules, and induced redistribution of tight junction ZO-1 and occludin and perijunctional F-actin. When mast cells were co-cultured with colonocytes, mast cell degranulation increased paracellular permeability of colonocytes. This was prevented by a tryptase inhibitor. We determined the role of ERK1/2 and of beta-arrestins, which recruit ERK1/2 to PAR2 in endosomes and retain ERK1/2 in the cytosol, on PAR2-mediated alterations in permeability. An ERK1/2 inhibitor abolished the effects of PAR2 agonist on permeability and redistribution of F-actin. Down-regulation of beta-arrestins with small interfering RNA inhibited PAR2-induced activation of ERK1/2 and suppressed PAR2-induced changes in permeability. Thus, mast cells signal to colonocytes in a paracrine manner by release of tryptase and activation of PAR2. PAR2 couples to beta-arrestin-dependent activation of ERK1/2, which regulates reorganization of perijunctional F-actin to increase epithelial permeability. These mechanisms may explain the increased epithelial permeability of the intestine during stress and inflammation.
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Stressful stimuli can enhance the permeability of the intestinal epithelium, which allows bacterial antigens to penetrate the gut epithelium and triggers an immune response in the intestinal mucosa.
“For example, several studies have demonstrated that stressful stimuli can enhance the permeability of the intestinal epithelium, which allows bacterial antigens to penetrate the gut epithelium and triggers an immune response in the intestinal mucosa.23-27”
From Principles and clinical implications of the brain-gut-enteric microbiota axis (2009) · cites this paper as [27]
MC proteases such as tryptase induce barrier dysfunction via alternate signaling mechanisms.
“MC proteases such as tryptase induce barrier dysfunction via alternate signaling mechanisms [31].”
From CRF induces intestinal epithelial barrier injury via the release of mast cell proteases and TNF-α (2012) · cites this paper as [31]
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- Authors
- Jacob, C., Yang, P.-C., Darmoul, D., Amadesi, S., Saito, T., Cottrell, G. S., Coelho, A.-M., Singh, P., Grady, E. F., Perdue, M., & Bunnett, N. W.
- Affiliations
- University of California, San Francisco (US)
- McMaster University (CA)
- Corresponding author
- Bunnett, Nigel W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-09
- Volume
- 280
- Issue
- 36
- Pages
- 31936-31948
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2118752824
- Cited by
- 334
- References
- 46
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 7 · 2023: 13 · 2022: 19 · 2021: 11 · 2020: 24 · 2019: 21 · 2018: 15 · 2017: 18 · 2016: 11 · 2015: 16 · 2014: 19 · 2013: 17 · 2012: 15
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 52388, DK-39957, DK 57840, DK 43207, R01DK057840, R01DK052388)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- tryptase, paracellular permeability, intestinal epithelial permeability, protease-activated receptor 2, colonic epithelial cells, tight junctions, beta-arrestin, ERK signaling, F-actin reorganization, mast cell degranulation, paracrine signaling, inflammation, stress, ZO-1, occludin, transepithelial electrical resistance
- MeSH terms
- beta-Arrestins, Actins, Calcium, Cell Line, Colon, Humans, Mast Cells, Permeability, Serine Endopeptidases, Signal Transduction, Coculture Techniques, Tight Junctions, Arrestins, Mitogen-Activated Protein Kinase 1, RNA, Small Interfering, Receptor, PAR-2, Mitogen-Activated Protein Kinase 3, Tryptases
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