Abstract
Aryl hydrocarbon receptor (AhR), a transcription factor activated by a large number of natural and synthetic agents, modulates the activity of immune cells in the gut and represents an important link between the environment and immune-mediated pathologies. In this study, we investigated the role of AhR in celiac disease (CD), a gluten-driven enteropathy. AhR expression was evaluated in intestinal biopsies taken from patients with CD and controls by real-time polymerase chain reaction (PCR), immunohistochemistry and flow cytometry. AhR was also analyzed in ex vivo organ cultures of duodenal biopsies taken from inactive CD patients incubated in presence or absence of peptic-tryptic digest of gliadin. IFN-γ, TNF-α, granzyme B, and perforin expression was evaluated in anti-CD3/CD28-activated intestinal lamina propria mononuclear cells (LPMC) and intestinal intra-epithelial cells (IEL) of active CD patients cultured in the presence or absence of the AhR agonist 6-formylindolo(3, 2-b)carbazole (Ficz). Finally, the protective role of AhR was evaluated in a mouse model of poly I:C-driven small intestine damage. AhR RNA transcripts were reduced in active CD samples as compared to inactive CD and normal controls. Flow cytometry confirmed such results and showed a reduction of AhR in both IEL and LPMC of active CD patients. The addition of a peptic-tryptic digest of gliadin to ex vivo organ cultures of duodenal biopsies taken from inactive CD patients reduced AhR expression. Treatment of CD IEL and LPMC with Ficz reduced the levels of inflammatory cytokines, granzyme B and perforin. Mice injected with Ficz were protected against poly I:C-induced intestinal lesions. Our findings suggest that defective AhR-driven signals could contribute to amplify pathogenic responses in the gut of CD patients.
Highlights
Celiac disease (CD) is a chronic enteropathy triggered by dietary gluten present in wheat, barley, and rye [1, 2]
To assess whether celiac disease (CD)-related inflammation is characterized by an altered expression of Aryl hydrocarbon receptor (AhR), we initially evaluated AhR RNA transcripts in mucosal biopsies taken from active CD patients, inactive CD patients and controls
The number of cells purified from duodenal biopsy samples was not sufficient to further assess the expression of AhR in additional cell types, which have been associated with AhR function in other systems [27]
Summary
Celiac disease (CD) is a chronic enteropathy triggered by dietary gluten present in wheat, barley, and rye [1, 2]. Ingestion of gluten associates with activation of both innate and adaptive immune responses and production of elevated levels of inflammatory cytokines, with the downstream effect of causing villous atrophy and crypt hyperplasia [3]. Gluten can stimulate innate immune cells and epithelial cells to produce IL-15, which in turn activates cytotoxic cells, such as natural killer (NK) cells and CD8+ T lymphocytes [6]. These activated cytotoxic cells bind to specific stress ligands on enterocytes, with the ultimate result of epithelial cell killing and villous atrophy [8]. It has been demonstrated that IL-10 polymorphisms, which lead to reduced production of IL-10, are associated with an earlyonset of CD and a more clinically severe form of intestinal lesions [11]
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