Project

Back to overview

The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating inflammasome activation: implications for chronic intestinal inflammation

English title The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating inflammasome activation: implications for chronic intestinal inflammation
Applicant Scharl Michael
Number 166381
Funding scheme Project funding (special)
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.04.2016 - 31.03.2019
Approved amount 428'102.00
Show all

All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (8)

Inflammasome; Protein tyrosine phosphatases; Inflammatory Bowel Disease; Mononuclear cells; Chronic intestinal inflammation; Epithelial barrier function; large nested project to SIBDC; Genetic variation within IBD risk genes

Lay Summary (German)

Lead
Die chronisch-entzündlichen Darmerkrankungen (CED) betreffen alleine in der Schweiz etwa 15‘000 Menschen. Sie entstehen aufgrund einer fehlregulierten Immunantwort des Körpers auf verschiedenste Antigene. Ihr Auftreten wird durch Mutationen in bestimmten Risikogenen gefördert. Ein solches Risikogen ist die Protein Tyrosin Phosphatase non-receptor type 2 (PTPN2). Dieses Molekül dürfte eine wichtige Rolle in der Regulation von Entzündungszellen, insbesondere Monozyten und Makrophagen, spielen.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Bis jetzt ist die Rolle von PTPN2 in der Entstehung der chronisch-entzündlichen Darmerkrankungen (CED) nicht geklärt. Wir gehen davon aus, dass PTPN2 eine entscheidende Rolle für die Funktion von Monozyten und Makrophagen spielt. In enger Zusammenarbeit mit der Schweizer IBD Kohorte wollen wir deshalb untersuchen (a) ob PTPN2 die Aktivierung des Inflammasoms in mononukleären Zellen reguliert, (b) ob Fehlfunktion von PTPN2 zu einer verminderten Immunantwort auf pathogene Darmbakterien führt und (c) ob die Anwesenheit der CED-assoziierten Genvarianten im PTPN2 Gen eine aberrante Aktivierung und Funktion des angeborenen Immunsystems zur Folge haben. Zur Beantwortung dieser Fragen werden wir zum einen in vitro Experimente mittels Zelllinien und zum anderen in vivo Experimente mittels verschiedener Mausmodelle durchführen. Um die Relevanz unserer Erkenntnisse auf die klinische Praxis übertragen zu können, sollen Gewebeproben sowie Zellen von Patienten der Schweizer IBD-Kohorte hinsichtlich der genannten Fragestellungen untersucht werden.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Untersuchungen dienen dazu, die Rolle von PTPN2 im Rahmen chronisch-entzündlicher Erkrankungen näher zu definieren. Hierdurch sollen wichtige Erkenntnisse über die Regulationsmechanismen von mononukleären Zellen im Rahmen dieser Erkrankungen gewonnen werden. Die Ergebnisse dürften wichtige Erkenntnisse für die Identifizierung neuer therapeutischer Ansatzpunkte in der Behandlung chronisch-entzündlicher Erkrankungen liefern. Dies könnte letztlich entscheidend zur Verbesserung der Behandlungsmöglichkeiten nicht nur von CED-Patienten, sondern auch von Patienten mit anderen chronisch-entzündlichen Erkrankungen, wie rheumatoider Arthritis, Psoriasis oder Typ-I-Diabetes beitragen.

Direct link to Lay Summary Last update: 30.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner
Spalinger Marianne R., Schmidt Thomas S.B., Schwarzfischer Marlene, Hering Larissa, Atrott Kirstin, Lang Silvia, Gottier Claudia, Geirnaert Annelies, Lacroix Christophe, Dai Xuezhi, Rawlings David J., Chan Andrew C., von Mering Christian, Rogler Gerhard, Scharl Michael (2019), Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner, in Journal of Clinical Investigation, 129(6), 2527-2541.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Declan McCole, University of California, Riverside United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. med. Stephan Vavricka Switzerland (Europe)
- Publication
Prof. Dr. Achim Weber, Institute for Surgical Pathology, USZ Switzerland (Europe)
- Publication
Prof. Dr. Christophe Lacroix, Institute of food, nutrition and health, ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Hans-Dietmar Beer, PhD, Clinic for Dermatology, University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Swiss IBD Cohort Study Group Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Thomas Kündig, Clinic for Dermatology, University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Burkhard Becher, Institute of Neuroimmunology, University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Dr. Gerhard Rogler, USZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
DDW 2018 Talk given at a conference Validation of a novel xenograft mouse model for intestinal fistulas 19.05.2018 Chicago, United States of America Bruckner Ramona;
FALK-Symposium Talk given at a conference Novel human gut xenograft mouse model for intestinal fistulas 06.10.2017 Berlin, Germany Bruckner Ramona;
ECCO Congress 2017 Talk given at a conference New human gut xenograft mouse model for intestinal fistulas 16.02.2017 Barcelona, Spain Bruckner Ramona;


Awards

Title Year
Gastroenterologie Preis of the Swiss Society of Gastroenterology, Switzerland 2018
Georg Friedrich Götz Preis der Universität Zürich 2018
Best Abstract Gastroenterology, Swiss Society of Gastroenterology, Switzerland 2017
Best Poster Award FALK-Symposium Berlin 2017
ECCO Best Digital Oral Presentation Award 2017 2017

Associated projects

Number Title Start Funding scheme
184753 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in the pathogenesis of colorectal carcinoma 01.04.2019 Project funding (Div. I-III)
154488 The Microbe-Host Interface: Molecular Mechanisms Mediating Protective and Pathological Innate and Adaptive Immune Responses within the Gut 01.11.2014 Sinergia
146204 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating the differentiation of CD4+, naive T-cells during chronic intestinal inflammation 01.04.2013 Project funding (special)
184753 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in the pathogenesis of colorectal carcinoma 01.04.2019 Project funding (Div. I-III)
148422 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2014 Cohort Studies Large

Abstract

Inflammatory bowel disease (IBD) is characterized by a chronic intestinal inflammation and impacts the life of up to 15’000 people alone in Switzerland. On a molecular level, genetic, environmental and bacterial factors contribute to IBD pathogenesis by causing a dysregulation of the immune system. It is well accepted that an aberrant cytokine secretion as well as a break-down of the intestinal epithelial barrier plays a key role for the onset and perpetuation of IBD. Dysfunction of the Nlrp3 inflammasome, a receptor for bacterial components and particulate materials, has been associated with the onset of colitis.Our recent studies implicated an essential role for the IBD susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in immune cell function. Our preliminary data strongly suggest a functional interaction between Nlrp3 and PTPN2. The exact role of PTPN2, also a risk factor for diabetes and rheumatoid arthritis, in the pathogenesis of IBD is unknown. Here, we will study whether PTPN2 is involved in the regulation and function of the Nlrp3 inflammasome.Our hypotheses supported by recent data are that:APTPN2 regulates inflammasome activation and function in epithelial and immune cells BLoss of PTPN2 impairs intestinal epithelial barrier function and host defence against bacteriaCInflammasome inhibition affects the functional consequences of PTPN2 dysfunction in vivoDPresence of the IBD-associated PTPN2 variants affects activation and function of the inflammasome causing an intestinal epithelial barrier defectWe will study A) whether dysfunction of PTPN2 affects activation and function of the inflammasome. Using cell lines and mouse models of intestinal inflammation we will assess a regulatory effect of PTPN2 on Nlrp3 inflammasome activation by molecular approaches, mass spectrometry and visual imaging. The relevance for PTPN2 for the regulation of the inflammasome will be demonstrated using PTPN2 knock-out (-/-) mice featuring a conditional PTPN2-/- in mononuclear (PTPN2flox/flox x LysMCre), dendritic (PTPN2flox/flox x CD11cCre) and intestinal epithelial cells (IEC; PTPN2flox/flox x villinCre). We will induce acute and chronic colitis in mice by treatment with dextran sodium sulphate (DSS), TNBS, applying a T-cell transfer colitis model or by back-crossing our mice into an IL-10-deficient background. B) We will further study, whether PTPN2 activity is critical for maintaining intestinal epithelial barrier function and controlling intestinal microbiota during health and colitis using PTPN2-/- mice. C) To directly demonstrate the physiological relevance of altered inflammasome activation in response to PTPN2-/- we will inhibit inflammasome function by blocking IL-1alpha and/or IL-1beta in our PTPN2-/- colitis mouse models using virus-like particle (VLP)-based vaccines against IL-1alpha and IL-1beta and respective monoclonal antibodies. (D) To study the importance of PTPN2 for regulating the Nlrp3 inflammasome in human disease, we will test whether presence of the IBD-associated PTPN2 variants affect activation and function of Nlrp3 inflammasome in primary human mononuclear, dendritic and IEC isolated from non-IBD control and IBD patients of the Swiss IBD cohort study. According to our hypotheses, loss of PTPN2 enhances activity of the Nlrp3 inflammasome and critically contributes to a dysregulatd immune response and a barrier break-down in response to bacterial components and particulate materials finally aggravating intestinal inflammation. Our findings will define the role for PTPN2 in the pathogenesis of chronic intestinal inflammation. They might help to identify potentially new targets for the treatment not only of IBD but also of other diseases featuring a chronic inflammation.
-