Carboxypeptidase E modulates intestinal immune homeostasis and protects against experimental colitis in mice

PLoS One. 2014 Jul 22;9(7):e102347. doi: 10.1371/journal.pone.0102347. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxypeptidase H / physiology*
  • Cell Movement / immunology
  • Cells, Cultured
  • Chromogranin B / metabolism
  • Colitis / chemically induced
  • Colitis / enzymology*
  • Colitis / immunology
  • Colon / enzymology
  • Colon / immunology
  • Dextran Sulfate
  • Homeostasis
  • Humans
  • Inflammatory Bowel Diseases / chemically induced
  • Inflammatory Bowel Diseases / enzymology*
  • Inflammatory Bowel Diseases / immunology
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / immunology
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology
  • Neuropeptide Y / metabolism
  • Protein Transport

Substances

  • Chromogranin B
  • Neuropeptide Y
  • Dextran Sulfate
  • Carboxypeptidase H

Grant support

This work was supported by the Section of Medicine, University of Lübeck (E06-2011; P01-2012 to C.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.