Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice.
Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier...
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doaj-d91c14fc92564a9aab5180ab655ceb892020-11-24T21:30:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10234710.1371/journal.pone.0102347Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice.Florian BärBandik FöhRené PagelTorsten SchröderHeidi SchlichtingMisa HiroseSusanne LemckeAntje KlingerPeter KönigChristian M KarstenJürgen BüningHendrik LehnertKlaus FellermannSaleh M IbrahimChristian SinaEnteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe-/- mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe-/- mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe-/- mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD.http://europepmc.org/articles/PMC4106776?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Florian Bär Bandik Föh René Pagel Torsten Schröder Heidi Schlichting Misa Hirose Susanne Lemcke Antje Klinger Peter König Christian M Karsten Jürgen Büning Hendrik Lehnert Klaus Fellermann Saleh M Ibrahim Christian Sina |
spellingShingle |
Florian Bär Bandik Föh René Pagel Torsten Schröder Heidi Schlichting Misa Hirose Susanne Lemcke Antje Klinger Peter König Christian M Karsten Jürgen Büning Hendrik Lehnert Klaus Fellermann Saleh M Ibrahim Christian Sina Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice. PLoS ONE |
author_facet |
Florian Bär Bandik Föh René Pagel Torsten Schröder Heidi Schlichting Misa Hirose Susanne Lemcke Antje Klinger Peter König Christian M Karsten Jürgen Büning Hendrik Lehnert Klaus Fellermann Saleh M Ibrahim Christian Sina |
author_sort |
Florian Bär |
title |
Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice. |
title_short |
Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice. |
title_full |
Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice. |
title_fullStr |
Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice. |
title_full_unstemmed |
Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice. |
title_sort |
carboxypeptidase e modulates intestinal immune homeostasis and protects against experimental colitis in mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe-/- mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe-/- mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe-/- mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD. |
url |
http://europepmc.org/articles/PMC4106776?pdf=render |
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