Dataset Information

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.

SUBMITTER: Bar F

PROVIDER: S-EPMC4106776 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Bär Florian F Föh Bandik B Pagel René R Schröder Torsten T Schlichting Heidi H Hirose Misa M Lemcke Susanne S Klinger Antje A König Peter P Karsten Christian M CM Büning Jürgen J Lehnert Hendrik H Fellermann Klaus K Ibrahim Saleh M SM Sina Christian C

PloS one 20140722 7

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 specifi ...[more]

PMID: 25051500

Similar Datasets

Project description:Intestinal homeostasis is dynamically coordinated by various types of epithelial cells fulfilling their specific functions. Tuft cells as chemosensory cells have emerged as key players of the host response, such as innate immunity. Tuft cells are also critical for the restoration of intestinal architecture upon damage, thereby contributing to inflammatory bowel diseases (IBDs) characterized by defective intestinal barrier integrity. However, the molecular mechanism of how tuft cell homeostasis is controlled remains obscure. Recent studies have identified single-nucleotide polymorphisms in the inositol polyphosphate multikinase (IPMK) gene associated with IBD predisposition. IPMK, an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. To investigate the functional significance of IPMK in gut epithelium, we generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMKΔIEC) mice. Whereas IPMKΔIEC mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium (DSS)-induced colitis, with higher clinical colitis scores, and elevated epithelial barrier permeability. Surprisingly, no apparent defects in epithelial growth signaling pathway and inflammation were found in DSS-challenged, IPMK-deficient colons. Rather, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other intestinal epithelial cells. Ipmk deletion in the gut epithelium was found to reduce choline acetyltransferase but not cytokines (e.g., IL-25), suggesting selective loss of cholinergic signaling. Single-cell RNA-sequencing of mouse colonic tuft cells (EpCAM+/Siglec F+) and immunohistochemistry revealed three populations of tuft cells and further showed that, in IPMKΔIEC mice, a transcriptionally inactive tuft club cell population was markedly expanded, and neuronal-related tuft cells were relatively decreased, supporting the abnormal development of tuft cells without IPMK functions. Thus, IPMK acts as a physiological determinant of colonic tuft cell homeostasis, thereby mediating tissue regeneration upon injury.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure