TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration
Open accessAbstract
Recruitment of polymorphonuclear leukocytes (PMNs) into the lungs in response to inhaled pathogens is initiated by epithelial signaling, the activation of toll-like receptors (TLRs), and the production of the chemokine interleukin-8. To reach the site of infection, PMNs must be mobilized through epithelial junctions. Here, we demonstrate that Ca(2+) fluxes generated by TLR2 signals activate calpains, Ca(2+)-dependent cysteine proteases. These activated calpains cleave the transmembrane junctional proteins occludin and E-cadherin without breaching the integrity of the epithelial barrier. Calpain inhibitors decrease PMN transepithelial migration in response to TLR2 agonists both in vitro and in a mouse model of P. aeruginosa infection. Thus, TLR2 signaling in the airway not only induces chemokine expression to recruit PMNs, but also initiates cleavage of junctional proteins to accommodate transmigration of the recruited PMNs.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In vivo, PMNs would be recruited and activated through inflammasome-mediated signaling by IL-1β and calpain-mediated cleavage of paracellular junctional proteins.
“in vivo, PMNs would be recruited and activated through inflammasome-mediated signaling: by IL-1β and by calpain-mediated cleavage of paracellular junctional proteins to facilitate their recruitment [22].”
From Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes (2012) · cites this paper as [22]
USA300 induces Ca2+ flux in HaCaT cells required for calpain activity.
“as well as the generation of Ca 2+ flux (Figure 3B) required for calpain activity in response to USA300 [22].”
From Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes (2012) · cites this paper as [22]
Calpains participate in PMN recruitment across airway epithelial barriers, with Ca2+ flux induced through TLR2 signaling as the stimulus.
“We have previously found that calpains participate in PMN recruitment across airway epithelial barriers [22].In those studies, the stimulus for calpain activity was the Ca 2+ flux induced through TLR2 signaling”
From Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes (2012) · cites this paper as [22]
The requirement for intact bacteria likely reflects the contribution of staphylococcal lipoproteins and TLR2 signaling that also activate calpain activity in airway epithelial cells.
“The requirement for intact bacteria is likely to reflect the contribution of staphylococcal lipoproteins and TLR2 signaling that also activate calpain activity in airway epithelial cells airway (28).”
From Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity (2011) · cites this paper as [28]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Goll, D. E., Thompson, V. F., Li, H., WEI, W., & Cong, J. (2003) · Physiological Reviews · doi:10.1152/physrev.00029.2002 · Cited by 2,826 · see citing works
Matrix metalloproteinases as modulators of inflammation and innate immunity
Parks, W. C., Wilson, C. L., & López-Boado, Y. S. (2004) · Nature Reviews Immunology · doi:10.1038/nri1418 · Cited by 1,929 · see citing works
Signaling Mechanisms Regulating Endothelial Permeability
Mehta, D., & Malik, A. B. (2005) · Physiological Reviews · doi:10.1152/physrev.00012.2005 · Cited by 1,711 · see citing works
Complex Phenotype of Mice Lacking Occludin, a Component of Tight Junction Strands
Saitou, M., Furuse, M., Sasaki, H., Schulzke, J.-D., Fromm, M., Takano, H., Noda, T., & Tsukita, S. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.12.4131 · Cited by 1,195 · see citing works
Li, Q., Park, P. W., Wilson, C. L., & Parks, W. C. (2002) · Cell · doi:10.1016/s0092-8674(02)01079-6 · Cited by 752 · see citing works
Regulation of tight junctions and loss of barrier function in pathophysiology
Harhaj, N. S., & Antonetti, D. A. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2003.08.007 · Cited by 543 · see citing works
Regulating cell migration: calpains make the cut
Franco, S. J., & Anna Huttenlocher, A. (2005) · Journal of Cell Science · doi:10.1242/jcs.02562 · Cited by 495 · see citing works
Occludin: Structure, function and regulation
FELDMAN, G., Mullin, J. M., & RYAN, M. (2005) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2005.01.009 · Cited by 485 · see citing works
Recognition ofStaphylococcus aureusby the Innate Immune System
Fournier, B., & Philpott, D. J. (2005) · Clinical Microbiology Reviews · doi:10.1128/cmr.18.3.521-540.2005 · Cited by 475 · see citing works
Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1
Gómez, M. I., Lee, A., Reddy, B., Muir, A., Soong, G., Pitt, A., Cheung, A., & Prince, A. (2004) · Nature Medicine · doi:10.1038/nm1079 · Cited by 412 · see citing works
Self-citationTang, H. B., DiMango, E., Bryan, R. A., Gambello, M. J., Iglewski, B. H., Goldberg, J. B., & Prince, A. S. (1996) · Infection and Immunity · doi:10.1128/iai.64.1.37-43.1996 · Cited by 401 · see citing works
Self-citationThe ins and outs of E-cadherin trafficking
Bryant, D. M., & Stow, J. L. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.07.007 · Cited by 370 · see citing works
Shen, L., Weber, C. R., & Turner, J. R. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200711165 · Cited by 361 · see citing works
Neutrophil Migration Mechanisms, with an Emphasis on the Pulmonary Vasculature
Wagner, J. G., & Roth, R. A. (2000) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01456-x · Cited by 347 · see citing works
Huang, A. J. Y., Manning, J. E., Bandak, T. M., Ratau, M. C., Hanser, K. R., & Silverstein, S. C. (1993) · The Journal of Cell Biology · doi:10.1083/jcb.120.6.1371 · Cited by 339 · see citing works
McGuire, J. K., Li, Q., & Parks, W. C. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64318-0 · Cited by 323 · see citing works
Epithelial transport and barrier function in occludin-deficient mice
Schulzke, J., Gitter, A. H., Mankertz, J., Spiegel, S., Seidler, U. E., Amasheh, S., Saitou, M., Tsukita, S., & Fromm, M. (2005) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2005.01.008 · Cited by 320 · see citing works
Reutershan, J., Basit, A., Galkina, E., & Ley, K. F. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00477.2004 · Cited by 310 · see citing works
Knockdown of occludin expression leads to diverse phenotypic alterations in epithelial cells
Yu, A. S. L., McCarthy, K. M., Francis, S. A., McCormack, J. M., Lai, J., Rogers, R. A., Lynch, R. D., & Schneeberger, E. E. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00581.2004 · Cited by 307 · see citing works
Actin Depolymerization Disrupts Tight Junctions via Caveolae-mediated Endocytosis
Shen, L., & Turner, J. R. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-12-1089 · Cited by 302 · see citing works
Unique Structural Features That Influence Neutrophil Emigration Into the Lung
Burns, A. R., Smith, C. W., & Walker, D. C. (2003) · Physiological Reviews · doi:10.1152/physrev.00023.2002 · Cited by 298 · see citing works
Regulation of cell–cell junctions by the cytoskeleton
Mège, R., Gavard, J., & Lambert, M. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.08.004 · Cited by 269 · see citing works
Toll-Like Receptors in Normal and Cystic Fibrosis Airway Epithelial Cells
Muir, A. B., Soong, G., Sokol, S., Reddy, B. D., Gómez, M. I., van Heeckeren, A. M., & Prince, A. S. (2003) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2003-0329oc · Cited by 259 · see citing works
Self-citationSoong, G., Reddy, B. D., Sokol, S., Adamo, R., & Prince, A. S. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20773 · Cited by 211 · see citing works
Self-citationDisassembling adherens junctions: breaking up is hard to do
D’Souza‐Schorey, C. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.11.002 · Cited by 210 · see citing works
Hopkins, A. M., Walsh, S. V., Verkade, P., Boquet, P., & Nusrat, A. (2003) · Journal of Cell Science · doi:10.1242/jcs.00300 · Cited by 202 · see citing works
Wu, Z., Nybom, P., & Magnusson, K.-E. (2000) · Cellular Microbiology · doi:10.1046/j.1462-5822.2000.00025.x · Cited by 195 · see citing works
EGF induces macropinocytosis and SNX1-modulated recycling of E-cadherin
Bryant, D. M., Kerr, M. C., Hammond, L. A., Joseph, S. R., Mostov, K. E., Teasdale, R. D., & Stow, J. L. (2007) · Journal of Cell Science · doi:10.1242/jcs.000653 · Cited by 185 · see citing works
Rios‐Doria, J., Day, K. C., Kuefer, R., Rashid, M. G., Chinnaiyan, A. M., Rubin, M. A., & Day, M. L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208772200 · Cited by 180 · see citing works
The specific fates of tight junction proteins in apoptotic epithelial cells
Bojarski, C., Weiske, J., Schöneberg, T., Schröder, W., Mankertz, J., Schulzke, J., Florian, P., Fromm, M., Tauber, R., & Huber, O. (2004) · Journal of Cell Science · doi:10.1242/jcs.01071 · Cited by 173 · see citing works
Wachtel, M., Frei, K., Ehler, E., Fontana, A., Winterhalter, K. H., & Gloor, S. M. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.23.4347 · Cited by 172 · see citing works
Skerrett, S. J., Liggitt, H. D., Hajjar, A. M., & Wilson, C. B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.6.3377 · Cited by 172 · see citing works
Ratner, A. J., Bryan, R. A., Weber, A. J., Nguyen, S., Barnes, D., Pitt, A., Gelber, S. E., Cheung, A. L., & Prince, A. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007703200 · Cited by 169 · see citing works
Self-citationMüller, S. L., Portwich, M., Schmidt, A., Utepbergenov, D., Huber, O., Blasig, I. E., & Krause, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m411365200 · Cited by 169 · see citing works
Wan, H., Winton, H. L., Soeller, C., Stewart, G. A., Thompson, P. J., Gruenert, D. C., Cannell, M. B., Garrod, D. R., & Robinson, C. (2000) · European Respiratory Journal · doi:10.1034/j.1399-3003.2000.01514.x · Cited by 162 · see citing works
A dominant mutant of occludin disrupts tight junction structure and function
Bamforth, S. D., Kniesel, U., Wolburg, H., Engelhardt, B., & Risau, W. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.12.1879 · Cited by 147 · see citing works
Calpain regulates neutrophil chemotaxis
Lokuta, M. A., Nuzzi, P. A., & Anna Huttenlocher, A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0636533100 · Cited by 144 · see citing works
Occludin Modulates Transepithelial Migration of Neutrophils
Huber, D., Balda, M. S., & Matter, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5773 · Cited by 126 · see citing works
Shao, H., Chou, J.-H., Baty, C. J., Burke, N. A., Watkins, S. C., Stolz, D. B., & Wells, A. H. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02243-05 · Cited by 114 · see citing works
Stimulus-induced reorganization of tight junction structure: The role of membrane traffic
Yu, D., & Turner, J. R. (2007) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2007.07.027 · Cited by 93 · see citing works
Guttman, J. A., Samji, F. N., Li, Y., Vogl, A. W., & Finlay, B. B. (2006) · Infection and Immunity · doi:10.1128/iai.00721-06 · Cited by 89 · see citing works
Activation of Ca2+-Dependent Signaling by TLR2
Chun, J., & Prince, A. S. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.2.1330 · Cited by 78 · see citing works
Self-citationIchiyasu, H., McCormack, J. M., McCarthy, K. M., Dombkowski, D., Preffer, F. I., & Schneeberger, E. E. (2003) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2003-0370oc · Cited by 77 · see citing works
Group B Streptococcus Induces Macrophage Apoptosis by Calpain Activation
Fettucciari, K., Fetriconi, I., Mannucci, R., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.12.7542 · Cited by 72 · see citing works
Hurley, B. P., Siccardi, D., Mrsny, R. J., & McCormick, B. A. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.9.5712 · Cited by 71 · see citing works
Calpain-mediated regulation of platelet signaling pathways
Kuchay, S., & Chishti, A. H. (2007) · Current Opinion in Hematology · doi:10.1097/moh.0b013e3280ef68f8 · Cited by 58 · see citing works
Asymmetric Localization of Calpain 2 during Neutrophil Chemotaxis
Nuzzi, P. A., Senetar, M. A., & Anna Huttenlocher, A. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-09-0876 · Cited by 57 · see citing works
Dwyer‐Nield, L. D., Miller, A. C., Neighbors, B., et al. (1996) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1996.270.4.l526 · Cited by 37 · see citing works
Constantin, D., Cordenier, A., Robinson, K., et al. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02393.x · Cited by 32 · see citing works
Cuvelier, S. L., Paul, S., Shariat, N., Colarusso, P., & Patel, K. D. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041315 · Cited by 31 · see citing works
Katsube, M., Kato, T., Kitagawa, M., et al. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0907664 · Cited by 31 · see citing works
Endothelial Signaling in Leukocyte Transmigration
Hordijk, P. L. (2003) · Cell Biochemistry and Biophysics · doi:10.1385/cbb:38:3:305 · Cited by 30 · see citing works
Zhu, L., Li, X., Zeng, R., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0916 · Cited by 26 · see citing works
Regulation of lung neutrophil recruitment by VE-cadherin
Orrington-Myers, J., Gao, X., Kouklis, P. D., Broman, M., Rahman, A., Vogel, S. M., & Malik, A. B. (2006) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00502.2005 · Cited by 22 · see citing works
Truncated E‐cadherin potentiates cell death in prostate epithelial cells
Rios‐Doria, J., & Day, M. L. (2004) · The Prostate · doi:10.1002/pros.20179 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Intestinal mucosal barrier function in health and disease
Turner, J. R. (2009) · Nature reviews. Immunology · doi:10.1038/nri2653 · Cited by 3,952 · see citing works
Use of precision cut lung slices as a translational model for the study of lung biology
Liu, G., Betts, C., Cunoosamy, D. M., Åberg, P. M., Hornberg, J. J., Sivars, K. B., & Cohen, T. S. (2019) · Respiratory Research · doi:10.1186/s12931-019-1131-x · Cited by 206 · see citing works
Miyoshi, Y., Tanabe, S., & Suzuki, T. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00405.2015 · Cited by 115 · see citing works
Soong, G., Chun, J., Parker, D., & Prince, A. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis244 · Cited by 84 · see citing works
Self-citationSoong, G., Martin, F. J., Chun, J., Cohen, T. S., Ahn, D. S., & Prince, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.295386 · Cited by 73 · see citing works
Self-citation
- Authors
- Chun, J., & Prince, A.
- Affiliations
- Columbia University (US)
- Corresponding author
- Prince, Alice
- ORCID
- Prince, Alice
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 5
- Issue
- 1
- Pages
- 47-58
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC2768384
- OpenAlex
- W2033019676
- Cited by
- 87
- References
- 56
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 1 · 2013: 14 · 2012: 8
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL73989, R01HL073989)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK039693)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- TLR2 signaling, calpain, occludin, E-cadherin, neutrophil transmigration, polymorphonuclear leukocytes, airway epithelium, calcium flux, interleukin-8, Pseudomonas aeruginosa infection, epithelial barrier integrity, cysteine protease
- MeSH terms
- Animals, Calcium, Calpain, Cell Line, Cell Movement, Epithelial Cells, Humans, Intercellular Junctions, Leukocytes, Membrane Proteins, Mice, Inbred C57BL, Pseudomonas Infections, Cadherins, Pneumonia, Bacterial, Toll-Like Receptor 2, Mice, Cell Migration Assays, Leukocyte, Occludin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
