title: Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice.
abstract: 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.
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany; Institute of Anatomy, University of Lübeck, Lübeck, Germany.
authors: Florian
authors: F
authors: Bär
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Bandik
authors: B
authors: Föh
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: René
authors: R
authors: Pagel
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Torsten
authors: T
authors: Schröder
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Heidi
authors: H
authors: Schlichting
authors: Department of Dermatology, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Misa
authors: M
authors: Hirose
authors: Department of Dermatology, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Susanne
authors: S
authors: Lemcke
authors: Institute of Anatomy, University of Lübeck, Lübeck, Germany.
authors: Antje
authors: A
authors: Klinger
authors: Institute of Anatomy, University of Lübeck, Lübeck, Germany.
authors: Peter
authors: P
authors: König
authors: Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
authors: Christian M
authors: CM
authors: Karsten
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Jürgen
authors: J
authors: Büning
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Hendrik
authors: H
authors: Lehnert
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Klaus
authors: K
authors: Fellermann
authors: Department of Dermatology, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Saleh M
authors: SM
authors: Ibrahim
authors: Medical Department I, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors: Christian
authors: C
authors: Sina
mesh_terms: D000818:Animals; D043423:Carboxypeptidase H / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D053378:Chromogranin B / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D003106:Colon / Q000201:enzymology / Q000276:immunology; D016264:Dextran Sulfate; D006706:Homeostasis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology; D009478:Neuropeptide Y / Q000378:metabolism; D021381:Protein Transport
chemical_list: D053378:Chromogranin B; D009478:Neuropeptide Y; D016264:Dextran Sulfate; D043423:Carboxypeptidase H