Project

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Role of the chaperone gp96 for intestinal innate immunity, ER stress and the induction of tolerance

English title Role of the chaperone gp96 for intestinal innate immunity, ER stress and the induction of tolerance
Applicant Rogler Gerhard
Number 138410
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Cellular Biology, Cytology
Start/End 01.01.2012 - 31.05.2014
Approved amount 292'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Pathophysiology

Keywords (9)

gp96; antigen presenting cells; innate immunity; Crohn's disease; mucosal immunology; tolerance induction; ER stress; large nested project; Swiss Inflamatory Bowel Disease Cohort Study

Lay Summary (English)

Lead
Lay summary

Gp96 protein is a so called "heat shock protein" or "acute phase protein" normally located in the endoplasmatic reticulum (ER), a specific compartment of cells. It binds peptides (antigens) and can be secreted. Following re-uptake of the gp96-peptide-complex by antigen presenting cells (APCs) either immune responses or - in contrast - tolerance is induced depending on the local concentration of gp96. Gp96 also is involved in cellular stress reactions, the so-called ER stress reactions, that contribute to chronic inflammation in diseases such as inflammatory bowel diseases (IBD).

Intestinal macrophages (IMACs) represent one of the largest immune cell populations of the human body. They normally mediate tolerance against the bacterial flora in the gut. On the other hand those IMACs must react very quickly of not "normal" stool bacteria but pathogenic bacteria enter the mucosa. An impairment of those innate immune functions is associated with the pathogenesis of IBD in particular Crohn’s disease (CD). Studying this cell population since 1995 we found gp96 to be specifically induced during the mucosal development and differentiation of IMACsgp96 treatment ameliorates intestinal inflammation in mice which makes this protein also a target for therapeutic developments. Restitution of a normal function of IMACS would like result in a Crohn's disease treatment with few side effects.

As ER stress is supposed to play a role in IBD pathogenesis we will elucidate the function of gp96 during ER stress reactions in IBD mucosa. We aim to analyze

1) in which cells gp96 is essential for the maintenance of tolerance against commensal bacteria (“function in normal mucosa”) and
2) why the loss of gp96 protein in IMACs during CD contributes to the loss of tolerance (“contribution to CD pathogenesis”).

The long term goal of this project is a better understanding of mucosal tolerance and the development of new treatment options for chronic mucosal inflammatory diseases such as Crohn's disease.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Exogenous Heat Shock Protein gp96 Ameliorates CD4+CD62L+ T-Cell-mediated Transfer Colitis.
Fischbeck A Schreiter K Leucht K Frey-Wagner I Lang S Hausmann M Fried M Falk W Rogler G. (2014), Exogenous Heat Shock Protein gp96 Ameliorates CD4+CD62L+ T-Cell-mediated Transfer Colitis., in Inflamm Bowel Dis, epub ahead of print(epub ahead), epub ahead-epub ahead.
Regulation of the expression of chaperone gp96 in macrophages and dendritic cells.
Wolfram L Fischbeck A Frey-Wagner I Wojtal KA Lang S Fried M Vavricka SR Hausmann M Rogler G (2013), Regulation of the expression of chaperone gp96 in macrophages and dendritic cells., in PLoS One, 8, e76350.

Collaboration

Group / person Country
Types of collaboration
Prof. Jörg Dieter Schulzke Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Declan McCole United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
Ehrenpreis der Schweizer Gesellschaft für Gastroenterologie 2013

Associated projects

Number Title Start Funding scheme
120312 Role of the chaperone gp96 for intestinal barrier function and the induction of tolerance 01.07.2008 Project funding (Div. I-III)
148422 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2014 Cohort Studies Large
120312 Role of the chaperone gp96 for intestinal barrier function and the induction of tolerance 01.07.2008 Project funding (Div. I-III)

Abstract

We have studied the role of the chaperone gp96 for intestinal innate immunity and the induction of tolerance since 2 ½ years in our ongoing SNF project. Gp96 protein is a heat shock protein normally located in the endoplasmatic reticulum (ER). It binds peptides (antigens) and can be secreted. Following re-internalization of the gp96-peptide-complex by antigen presenting cells (APCs) the antigens can be transferred to MHC molecules mediating immune reactions or tolerance depending on the local concentration of gp96. Whereas it has been suggested that gp96 may be the major chaperone for Toll-like receptors (TLRs) our recent data from the first funding period demonstrate that this is likely not the case. However, we and others found that gp96 is involved in ER stress reactions that contribute to chronic inflammation in diseases such as inflammatory bowel diseases (IBD).Intestinal macrophages (IMACs) represent one of the largest macrophage populations of the human body. They constitute a tolerogenic cell type without expression of “typical” macrophage activation receptors. IMACs are of crucial importance for pathogen recognition at the mucosal surface and an impairment of their innate immune functions is associated with the pathogenesis of IBD in particular Crohn’s disease (CD). Studying this cell population since 1995 we found gp96 to be specifically induced during the differentiation of IMACs which could be confirmed in detailed studies during the last years. Gp96 is a chaperone which was reported to be essential for toll like receptor function. We demonstrated that gp96 treatment ameliorates intestinal inflammation in mice and generated cell specific conditional knock out mice for macrophages and epithelial cells to further study this function. Gp96 is also a target and regulator of ER stress as we could recently demonstrate. As ER stress is supposed to play a role in IBD pathogenesis it will be important to elucidate the exact function of gp96 during ER stress reactions in IBD mucosa. Based on our recent findings we aim to further analyze 1) in which cells gp96 is essential for the maintenance of tolerance against commensal bacteria (“function in normal mucosa”) and 2) why the loss of gp96 protein in IMACs during CD contributes to the loss of tolerance (“contribution to CD pathogenesis”).Specific aims A.Clarification of the uptake mechanisms for gp96 in iMACs and ivDCs. B. Impact of ER stress on gp96 function and vice versa in vitro and in vivo.C. T-cell response upon peptide presentation via gp96 and IMACs in vitro and in vivo. D. Role of gp96 expression in IEC and iMACs for colitis, intestinal barrier function and commensal flora in vivo.The long term goal will be a better understanding of mucosal tolerance and the development of new treatment options for chronic mucosal inflammatory diseases such as CD.
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