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9 results on '"European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013)"'

1. Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation

Author

Perrine Rousset, Laurent Alric, Anissa Edir, Chrystelle Bonnart, Jean-Paul Motta, Céline Deraison, David Sagnat, Elena F. Verdu, Derek M. McKay, Corinne Rolland, Emmanuel Mas, Laura Guiraud, Delphine Bonnet, Nathalie Vergnolle, Muriel Quaranta-Nicaise, Etienne Buscail, Ana Carolina Rodrigues Florence, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Toulouse [Toulouse], McMaster University [Hamilton, Ontario], University of Calgary, ANR JCJC-11JSV1 001 01, AOL-MICILIP project, ANR-12-BSV1-0030,ELAPROB-IBD,Mecanismes d'action des probiotiques recombinants pour l'Elafine: Leur utilisation possible pour traiter les maladies inflammatoires chroniques de l'intestin?(2012), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), European Project: 627487,EC:FP7:PEOPLE,FP7-PEOPLE-2013-IOF,EPIMACASE(2014), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), SEGUIN, Nathalie, BLANC - Mecanismes d'action des probiotiques recombinants pour l'Elafine: Leur utilisation possible pour traiter les maladies inflammatoires chroniques de l'intestin? - - ELAPROB-IBD2012 - ANR-12-BSV1-0030 - BLANC - VALID, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, THE ROLE OF ELASTASE/ELASTASE INHIBITOR IN DIALOG BETWEEN INTESTINAL EPITHELIAL CELLS AND MACROPHAGES IN INFLAMMATORY BOWEL DISEASES CONTEXT - EPIMACASE - - EC:FP7:PEOPLE2014-08-06 - 2016-08-05 - 627487 - VALID, and Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID

Subjects
0301 basic medicine, Adult, Male, Proteases, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Colon, medicine.medical_treatment, Immunology, Inflammation, Disease, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Inflammatory bowel disease, Article, Tight Junctions, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Immunology and Allergy, Medicine, Humans, Intestinal Mucosa, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Immunity, Mucosal, Barrier function, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Elastase, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, Pathophysiology, digestive system diseases, 3. Good health, Up-Regulation, 030104 developmental biology, Cytokine, Cytokines, 030211 gastroenterology & hepatology, Female, medicine.symptom, Inflammation Mediators, business, Leukocyte Elastase, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.

Published
2021

2. Colitis Linked to Endoplasmic Reticulum Stress Induces Trypsin Activity Affecting Epithelial Functions

Author

Delphine Bonnet, Nathalie Vergnolle, Sylvain Kirzin, Corinne Rolland, Muriel Quaranta-Nicaise, Alexandre Denadai-Souza, Anissa Edir, Laurent Alric, Nuria Sola Tapias, Emmanuel Mas, Gilles Dietrich, Marlène Marcellin, Frédérick Barreau, Carla Cirillo, Céline Deraison, Claire Rolland-Fourcade, Odile Burlet-Schiltz, Chrystelle Bonnart, Catherine Blanpied, Guillaume Portier, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), CHU Toulouse [Toulouse], University of Calgary, ANR-11-JSV1-0001,IBD-ase,Identification des protéases impliquées dans les maladies inflammatoires chroniques de l'intestin et analyse moléculaire des conséquences de leur hyperactivité(2011), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
0301 basic medicine, Chemokine, Thapsigargin, Cell Culture Techniques, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Inflammatory bowel disease, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, trypsin-like proteases, 0302 clinical medicine, Crohn Disease, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Trypsin, Interleukin 8, sendoplasmic reticulum stress, Barrier function, biology, business.industry, Endoplasmic reticulum, Gastroenterology, intestinal epithelial cell, General Medicine, Endoplasmic Reticulum Stress, 3. Good health, Cell biology, Organoids, Enterocytes, 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Intestinal Absorption, chemistry, Unfolded protein response, biology.protein, Colitis, Ulcerative, 030211 gastroenterology & hepatology, medicine.symptom, permeability, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Background and Aims Intestinal epithelial cells [IECs] from inflammatory bowel disease [IBD] patients exhibit an excessive induction of endoplasmic reticulum stress [ER stress] linked to altered intestinal barrier function and inflammation. Colonic tissues and the luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown. We aimed to study the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions Methods The impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cell lines or organoids. Moreover, treating human intestinal cells with protease-activated receptor antagonists allowed us to investigate ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology. Results Colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apical trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 [CXCL8]. The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of protease-activated receptors 2 and 4. Conclusions Excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, promoting the development of inflammatory process.

Published
2021

3. Increased mucosal thrombin is associated with Crohn's disease and causes inflammatory damage through Protease-Activated Receptors activation

Author

Motta, Jean-Paul, Palese, Simone, Giorgio, Carmine, Chapman, Kevin, Denadai-Souza, Alexandre, Rousset, Perrine, Sagnat, David, Guiraud, Laura, Edir, Anissa, Seguy, Carine, Alric, Laurent, Bonnet, Delphine, Bournet, Barbara, Buscail, Louis, Gilletta, Cyrielle, Buret, Andre, Wallace, John, Hollenberg, Morley, Oswald, Eric, Barocelli, Elisabetta, Le Grand, Sylvie, Le Grand, Bruno, Deraison, Céline, Vergnolle, Nathalie, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CVasThera, University of Parma, University of Calgary, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées, Occitanie region grant ('contrat innovation' reference: DEI-SYNAPSE), MICILIP project (NCT01990716), cellular imaging facility TRI-CPTP, COLIC collection (DC-2015-2443), Alberta-Innovate Health Services (AIHS), FEDER funding (EU and Occitanie region: Nanorgan project), Antibe Therapeutics, UMS 006 (animal care facility, histopathology core facility), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), University of Parma = Università degli studi di Parma [Parme, Italie], SEGUIN, Nathalie, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, AgreenSkills+ - AGREENSKILLSPLUS - - EC:FP7:PEOPLE2014-05-05 - 2019-05-04 - 609398 - VALID, Università degli studi di Parma = University of Parma (UNIPR), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Toulouse (UT)

Subjects
Male, EXPRESSION, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Pyridines, colitis, Receptors, Proteinase-Activated, INHIBITION, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Lactones, Mice, Crohn Disease, MARKERS, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Rats, Wistar, AcademicSubjects/MED00260, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Science & Technology, Gastroenterology & Hepatology, Thrombin, protease-activated receptors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Original Articles, thrombin, Rats, Up-Regulation, inflammation, Case-Control Studies, barrier, Female, ALPHA-THROMBIN, epithelium, BOWEL DISEASES, Life Sciences & Biomedicine, ELASTASE, SYSTEM, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BACKGROUND AND AIMS: Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn's disease. METHODS: Thrombin activity was studied in tissues from Crohn's disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulphonic acid. RESULTS: Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both protease-activated receptors -1 and -4. Intracolonic administration of the thrombin inhibitor dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulphonic acid-induced colitis in rodent models. CONCLUSIONS: Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease. ispartof: JOURNAL OF CROHNS & COLITIS vol:15 issue:5 pages:787-799 ispartof: location:England status: published

Published
2020

4. Active thrombin produced by the intestinal epithelium controls mucosal biofilms

Author

Motta, Jean-Paul, Denadai-Souza, Alexandre, Sagnat, David, Guiraud, Laura, Edir, Anissa, Bonnart, Chrystelle, Sebbag, Mireille, Rousset, Perrine, Lapeyre, Ariane, Seguy, Carine, Mathurine-Thomas, Noa, Galipeau, Heather J, Bonnet, Delphine, Alric, Laurent, Buret, Andre G, Wallace, John L, Dufour, Antoine, Verdu, Elena F, Hollenberg, Morley D, Oswald, Eric, Serino, Matteo, Deraison, Celine, Vergnolle, Nathalie, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Farncombe Family Digestive Health Research Institute [Hamilton, ON, Canada], McMaster University [Hamilton, Ontario], Service de médecine interne et maladies digestives [CHU Toulouse], CHU Toulouse [Toulouse], Department of Biological Sciences [Calgary], University of Calgary, Departments of Physiology & Pharmacology, and Medicine [Calgary, Canada] (School of Medicine), This work was supported by a grant from the European Research Council (ERC- 310973 PIPE) to NV. Tissue collection was originally sponsored by the University Hospital of Toulouse for regulatory and ethic submission, and by a grant from the delegation régionale à la recherche clinique des hôpitaux de Toulouse, through the MICILIP project. The COLIC collection (DC-2015-2443) was also used in the present study. The work used the Aninfimip core facility equipments, supported by Equipex funds from the National 'Investments for the future' program (ANR-11-EQPX-0003). JPM was funded by postdoctoral fellowships from the Alberta-Innovate Health Services (AIHS) and from EU’s Seventh Framework Programme N° FP7-609398 (AgreenSkills + contract). EFV holds a CRC and is Supported by CIHR MOP# 142773 and a CCC grant in Aid. Equipment acquired thanks to FEDER funding (EU and Occitanie region: Nanorgan project) were used in the present study., ANR-11-EQPX-0003/11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Médecine Interne et immunologie clinique [CHU Toulouse], Pôle Maladies de l'appareil digestif [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), MOTTA, Jean-Paul, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, and AgreenSkills+ - AGREENSKILLSPLUS - - EC:FP7:PEOPLE2014-05-05 - 2019-05-04 - 609398 - VALID

Subjects
EXPRESSION, BACTERIAL BIOFILMS, Colon, Science, VITAMIN-K DEFICIENCY, Urinary Bladder, HYDROGEN-SULFIDE, Epithelium, Article, Cell Line, Mice, Biologie animale, Animals, Homeostasis, Humans, PROTEASE INHIBITION, Intestinal Mucosa, lcsh:Science, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Lung, Skin, Animal biology, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, FLORA, Bacteria, Microbiota, GUT MICROBIOTA, Thrombin, SPATIAL-ORGANIZATION, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Bacterial host response, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Gastrointestinal Microbiome, Multidisciplinary Sciences, Mice, Inbred C57BL, Médecine vétérinaire et santé animal, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Biofilms, Colonic Neoplasms, Models, Animal, Science & Technology - Other Topics, lcsh:Q, Veterinary medicine and animal Health, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, GENERATION, COLITIS, circulatory and respiratory physiology
Abstract

Proteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin., The roles played by thrombin in the human intestinal mucosa are unclear. Here, the authors show that the commensal microbiota modulates epithelial production of active thrombin, which controls biofilm growth and contributes to protection of the mucosa from bacterial invasion.

Published
2019

5. FAK alternative splice mRNA variants expression pattern in colorectal cancer

Author

Devaud, Christel, Tilkin-Mariamé, Anne-Françoise, Vignolle-Vidoni, Alix, Souleres, Philippine, Denadai-Souza, Alexandre, Rolland, Corinne, Duthoit, Christine, Blanpied, Catherine, Chabot, Sophie, Bouillé, Pascale, Lluel, Philippe, Vergnolle, Nathalie, Racaud-Sultan, Claire, Ferrand, Audrey, Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vectalys SAS, Urosphère SAS, Ligue Regionale contre le Cancer, Region Midi-Pyrenees / Occitanie, Equipex 'Investissements d'avenir' funds (ANR-11-EQPX-0003), Urosphere, ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), UROsphere S.A.S., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Faculte des Sciences Pharmaceutiques, Racaud-Sultan, Claire, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT)

Subjects
Lung Neoplasms, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Molecular Cancer Biology, Mice, alternative splicing, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, RNA Isoforms, Animals, Humans, Neoplasm Invasiveness, metastases, FAK, Liver Neoplasms, HCT116 Cells, digestive system diseases, Up-Regulation, Gene Expression Regulation, Neoplastic, Focal Adhesion Kinase 1, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, biological phenomena, cell phenomena, and immunity, Colorectal Neoplasms, HT29 Cells, Neoplasm Transplantation, Autre (Sciences du Vivant)
Abstract

The Focal adhesion kinase (FAK) is a ubiquitous cytoplasmic tyrosine‐kinase promoting tumor progression and metastasis processes by acting in cancer cells and their tumor microenvironment partners. FAK overexpression in primary colon tumors and their metastasis is associated to poor colorectal cancer (CRC) patients’ outcome. Eight FAK mRNA alternative splice variants have been described and contribute to additional level of FAK activity regulation, some of them corresponding to overactivated FAK isoforms. To date, FAK mRNA alternative splice variants expression and implication in CRC processes remain unknown. Here, using different human CRC cells lines displaying differential invasive capacities in an in vivo murine model recapitulating the different steps of CRC development from primary tumors to liver and lung metastasis, we identified three out of the eight mRNA variants (namely FAK0, FAK28 and FAK6) differentially expressed along the CRC process and the tumor sites. Our results highlight an association between FAK0 and FAK6 expressions and the metastatic potential of the most aggressive cell lines HT29 and HCT116, suggesting that FAK0 and FAK6 could represent aggressiveness markers in CRC. Our findings also suggest a more specific role for FAK28 in the interactions between the tumors cells and their microenvironment. In conclusion, targeting FAK0, the common form of FAK, might not be a good strategy based on the numerous roles of this kinase in physiological processes. In contrast, FAK6 or FAK28 splice variants, or their corresponding protein isoforms, may putatively represent future therapeutic target candidates in the development of CRC primary tumors and metastasis., What's new? Overexpression of the focal adhesion kinase (FAK) is associated with poor outcome in patients with colorectal cancer but the role of the eight splice variants of FAK remains unknown. Here the authors correlated FAK splice variant expression in colorectal tumor cell lines with invasiveness in mouse models. FAK0 and FAK6 splice variant expression was associated with higher aggressiveness and metastatic potential, underscoring that distinct FAK splice variants may represent new targets in the development of drugs against colorectal cancer and associated metastasis.

Published
2019

6. Sexual dimorphism in PAR2-dependent regulation of primitive colonic cells

Author

Noguerol, Julie, Roustan, Pierre-Jean, N’Taye, Mikael, Delcombel, Léo, Rolland, Corinne, Guiraud, Laura, Sagnat, David, Edir, Anissa, Bonnart, Chrystelle, Denadai-Souza, Alexandre, Deraison, Céline, Vergnolle, Nathalie, Racaud-Sultan, Claire, Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fond Unique Interministeriel (FUI) program by the Région Midi-Pyrénées, the Banque Publique d’Investissement (BPI) de France, Fonds Européens de Développement Régional (FEDER), (ANR-11-EQPX-0003), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Racaud-Sultan, Claire, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT)

Subjects
Genetics & Heredity, EXPRESSION, HOMEOSTASIS, Science & Technology, Protease-activated receptor, lcsh:QP1-981, lcsh:R, lcsh:Medicine, Biotechnologies, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:Physiology, GSK3, Endocrinology & Metabolism, Sexual dimorphism, Médecine vétérinaire et santé animal, Colon primitive cells, ONSET, SURVIVAL, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Veterinary medicine and animal Health, Life Sciences & Biomedicine, STEM-CELLS
Abstract

BACKGROUND: Sexual dimorphism in biological responses is a critical knowledge for therapeutic proposals. However, gender differences in intestinal stem cell physiology have been poorly studied. Given the important role of the protease-activated receptor PAR2 in the control of colon epithelial primitive cells and cell cycle genes, we have performed a sex-based comparison of its expression and of the effects of PAR2 activation or knockout on cell proliferation and survival functions. METHODS: Epithelial primitive cells isolated from colons from male and female mice were cultured as colonoids, and their number and size were measured. PAR2 activation was triggered by the addition of SLIGRL agonist peptide in the culture medium. PAR2-deficient mice were used to study the impact of PAR2 expression on colon epithelial cell culture and gene expression. RESULTS: Colonoids from female mice were more abundant and larger compared to males, and these differences were further increased after PAR2 activation by specific PAR2 agonist peptide. The proliferation of male epithelial cells was lower compared to females but was specifically increased in PAR2 knockout male cells. PAR2 expression was higher in male colon cells compared to females and controlled the gene expression and activation of key negative signals of the primitive cell proliferation. This PAR2-dependent brake on the proliferation of male colon primitive cells was correlated with stress resistance. CONCLUSIONS: Altogether, these data demonstrate that there is a sexual dimorphism in the PAR2-dependent regulation of primitive cells of the colon crypt. ispartof: BIOLOGY OF SEX DIFFERENCES vol:10 issue:1 ispartof: location:England status: published

Published
2019

7. Neurons and Glia in the Enteric Nervous System and Epithelial Barrier Function

Author

Nathalie Vergnolle, Carla Cirillo, Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Catholique de Louvain = Catholic University of Louvain (UCL), the Region Midi-Pyrenees, Region Occitanie, European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), ProdInra, Migration, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Epithelial barrier, Neurons, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Physiology, Chemistry, education, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Epithelial Cells, Review, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Enteric Nervous System, Cell biology, Intestines, 03 medical and health sciences, 030104 developmental biology, Epithelial barrier function, Animals, Humans, Enteric nervous system, Neuroglia, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; The intestinal epithelial barrier is the largest exchange surface between the body and the external environment. Its functions are regulated by luminal, and also internal, components including the enteric nervous system. This review summarizes current knowledge about the role of the digestive “neuronal-glial-epithelial unit” on epithelial barrier function.

Published
2018

8. Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism

Author

Sébert, Morgane, Denadai‐Souza, Alexandre, Quaranta, Muriel, Racaud‐Sultan, Claire, Chabot, Sophie, Lluel, Philippe, Monjotin, Nicolas, Alric, Laurent, Portier, Guillaume, Kirzin, Sylvain, Bonnet, Delphine, Ferrand, Audrey, Vergnolle, Nathalie, Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Urosphère SAS, UROsphere S.A.S., Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Faculte des Sciences Pharmaceutiques, Centre de Recherche Pierre Fabre, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Chirurgie Générale et Digestive [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE, European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Organoids / cytology, Cell Survival / drug effects, Receptors Thrombin / metabolism, Cell Survival, Colon, EPITHELIUM, Apoptosis, Receptor PAR-1 / metabolism, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Apoptosis / drug effects, Organoids / drug effects, CELL-PROLIFERATION, CLONING, ANTAGONISTS, INJURY, Humans, Receptor, PAR-1, Pharmacology & Pharmacy, Cells, Cultured, Cell Proliferation, Colon / cytology, Science & Technology, Thrombin, ABERRANT EXPRESSION, Research Papers, CONCISE GUIDE, CANCER, Thrombin / pharmacology, Organoids, Organoids / growth & development, Colon / drug effects, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cell Proliferation / drug effects, Receptors, Thrombin, Cells Cultured, Life Sciences & Biomedicine, STEM-CELLS, Research Paper, INFLAMMATORY-BOWEL-DISEASE
Abstract

BACKGROUND AND PURPOSE: Thrombin is massively released upon tissue damage associated with bleeding or chronic inflammation. The effects of this thrombin on tissue regrowth and repair has been scarcely addressed and only in cancer cell lines. Hence, the purpose of the present study was to determine thrombin's pharmacological effects on human intestinal epithelium growth, proliferation and apoptosis, using three-dimensional cultures of human colon organoids. EXPERIMENTAL APPROACH: Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL-1 of thrombin, in the presence or not of protease-activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed. KEY RESULTS: Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger structures releasing cell debris and apoptotic cells. The size of budding structures, metabolic activity and proliferation were significantly reduced in organoid cultures exposed to thrombin, while apoptosis was dramatically increased. Both PAR1 and PAR4 antagonists inhibited apoptosis regardless of thrombin doses. Thrombin-induced inhibition of proliferation and metabolic activity were reversed by PAR4 antagonist for thrombin's lowest dose and by PAR1 antagonist for thrombin's highest dose. CONCLUSIONS AND IMPLICATIONS: Overall, our data suggest that the presence of thrombin in the vicinity of human colon epithelial cells favours their maturation at the expense of their regenerative capacities. Our data point to thrombin and its two receptors PAR1 and PAR4 as potential molecular targets for epithelial repair therapies. ispartof: BRITISH JOURNAL OF PHARMACOLOGY vol:175 issue:18 pages:3656-3668 ispartof: location:England status: published

Published
2018

9. Functional Proteomic Profiling of Secreted Serine Proteases in Health and Inflammatory Bowel Disease

Author

Alexandre Denadai-Souza, Chrystelle Bonnart, Núria Solà Tapias, Marlène Marcellin, Brendan Gilmore, Laurent Alric, Delphine Bonnet, Odile Burlet-Schiltz, Morley D. Hollenberg, Nathalie Vergnolle, Céline Deraison, Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Queen's University [Belfast] (QUB), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Chercheur indépendant, Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), School of Pharmacy, Queen's University Belfast, Belfast, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut de Recherche pour le Développement (IRD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Schiltz, Odile, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
Proteomics, Cathepsin G, lcsh:Medicine, approche protéomique, Article, PROBES, serine, SDG 3 - Good Health and Well-being, Tandem Mass Spectrometry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], BINDING, Humans, PROTEINASE-ACTIVATED RECEPTOR-2, Intestinal Mucosa, lcsh:Science, General, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Science & Technology, Gene Expression Profiling, lcsh:R, Thrombin, CATHEPSIN-G, protéase, pathophysiologie, Proteases, Inflammatory Bowel Diseases, maladie inflammatoire intestinale, digestive system diseases, Up-Regulation, Multidisciplinary Sciences, Hépatologie et Gastroentérologie, Mechanisms of disease, Gene Expression Regulation, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Science & Technology - Other Topics, Hépatology and Gastroenterology, lcsh:Q, Serine Proteases, INHIBITORS, ENZYMES, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, COLITIS, Chromatography, Liquid
Abstract

While proteases are essential in gastrointestinal physiology, accumulating evidence indicates that dysregulated proteolysis plays a pivotal role in the pathophysiology of inflammatory bowel disease (IBD). Nonetheless, the identity of overactive proteases released by human colonic mucosa remains largely unknown. Studies of protease abundance have primarily investigated expression profiles, not taking into account their enzymatic activity. Herein we have used serine protease-targeted activity-based probes (ABPs) coupled with mass spectral analysis to identify active forms of proteases secreted by the colonic mucosa of healthy controls and IBD patients. Profiling of (Pro-Lys)-ABP bound proteases revealed that most of hyperactive proteases from IBD secretome are clustered at 28-kDa. We identified seven active proteases: the serine proteases cathepsin G, plasma kallikrein, plasmin, tryptase, chymotrypsin-like elastase 3 A, and thrombin and the aminopeptidase B. Only cathepsin G and thrombin were overactive in supernatants from IBD patient tissues compared to healthy controls. Gene expression analysis highlighted the transcription of genes encoding these proteases into intestinal mucosae. The functional ABP-targeted proteomic approach that we have used to identify active proteases in human colonic samples bears directly on the understanding of the role these enzymes may play in the pathophysiology of IBD. ispartof: SCIENTIFIC REPORTS vol:8 issue:1 ispartof: location:England status: published

Published
2017

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