Crohn’s disease-derived monocytes fail to induce Paneth cell defensins

Crohn’s disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides essential for the host barrier, principally human α-defensin 5 (HD5) and HD6. Patients with CD of th...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-11, Vol.112 (45), p.14000-14005
Main Authors: Courth, Lioba F., Ostaff, Maureen J., Mailänder-Sánchez, Daniela, Malek, Nisar P., Stange, Eduard F., Wehkamp, Jan
Format: Article
Language:English
Subjects:
alpha-Defensins - secretion
Biological Sciences
Bone marrow
Cells
Crohn Disease - microbiology
Crohn Disease - physiopathology
Crohns disease
Cytokines
DNA Primers - genetics
HEK293 Cells
Humans
Ileum - metabolism
Ileum - microbiology
Immunohistochemistry
Ligands
Microbiota - immunology
Monocytes - immunology
Monocytes - metabolism
Paneth Cells - secretion
Peptides
Real-Time Polymerase Chain Reaction
Receptor Cross-Talk - immunology
Statistics, Nonparametric
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Crohn’s disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides essential for the host barrier, principally human α-defensin 5 (HD5) and HD6. Patients with CD of the ileum are characterized by reduced constitutive expression of these peptides and, accordingly, compromised antimicrobial barrier function. Here, we present a previously unidentified regulatory mechanism of Paneth cell defensins. Using cultures of human ileal tissue, we showed that the secretome of peripheral blood mononuclear cells (PBMCs) from healthy controls restored the attenuated Paneth cell α-defensin expression characteristic of patients with ileal CD. Analysis of the Wnt pathway in both cultured biopsies and intestinal epithelial cells implicated Wnt ligands driving the PBMC effect, whereas various tested cytokines were ineffective. We further detected another defect in patients with ileal CD, because the PBMC secretomes derived from patients with CD were unable to restore the reduced HD5/HD6 expression. Accordingly, analysis of PBMC subtypes showed that monocytes of patients with CD express significantly lower levels of canonical Wnt ligands, including Wnt3, Wnt3a, Wnt1, and wntless Wnt ligand secretion mediator (Evi/Wls). These studies reveal an important cross-talk between bone marrow-derived cells and epithelial secretory Paneth cells. Defective Paneth cell-mediated innate immunity due to inadequate Wnt ligand stimulation by monocytes provides an additional mechanism in CD. Because defects of Paneth cell function stemming from various etiologies are overcome by Wnt ligands, this mechanism is a potential therapeutic target for this disease.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1510084112