title: Crohn's disease-derived monocytes fail to induce Paneth cell defensins.
abstract: 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.
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, 72076 Tuebingen, Germany;
authors.forename: Lioba F
authors.initials: LF
authors.lastname: Courth
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, 70376 Stuttgart, Germany;
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Ostaff
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, 72076 Tuebingen, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Mailänder-Sánchez
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, 72076 Tuebingen, Germany;
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: Department of Gastroenterology, Robert Bosch Hospital, 70376 Stuttgart, Germany.
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
authors.affiliation: Department of Internal Medicine I, University Hospital Tuebingen, 72076 Tuebingen, Germany; jan.wehkamp@med.uni-tuebingen.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
mesh_terms: D003424:Crohn Disease / Q000382:microbiology / Q000503:physiopathology*; D017931:DNA Primers / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism* / Q000382:microbiology; D007150:Immunohistochemistry; D064307:Microbiota / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D019879:Paneth Cells / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000276:immunology*; D018709:Statistics, Nonparametric; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D023084:alpha-Defensins
keywords: Crohn’s disease; Paneth cells; Wnt ligands; ileum; α-defensins