Abstract
Innate lymphoid cells (ILCs) are an emerging family of innate hematopoietic cells producing inflammatory cytokines and involved in the pathogenesis of several immune-mediated diseases. The aim of this study was to characterize the tissue distribution of ILCs in celiac disease (CD), a gluten-driven enteropathy, and analyze their role in gut tissue damage. ILC subpopulations were analyzed in lamina propria mononuclear cells (LPMCs) isolated from duodenal biopsies of CD patients and healthy controls (CTR) and jejunal specimens of patients undergoing gastro-intestinal bypass by flow cytometry. Cytokines and Toll-like receptors (TLR) were assessed in ILCs either freshly isolated or following incubation of control LPMC with peptidoglycan, poly I:C, or CpG, the agonists of TLR2, TLR3, or TLR9 respectively, by flow cytometry. The role of ILCs in gut tissue damage was evaluated in a mouse model of poly I:C-driven small intestine atrophy. Although the percentage of total ILCs did not differ between CD patients and CTR, ILCs producing TNF-α and IFN-γ were more abundant in CD mucosa compared to controls. ILCs expressed TLR2, TLR3 and TLR9 but neither TLR7 nor TLR4. Stimulation of LPMC with poly I:C but not PGN or CpG increased TNF-α and IFN-γ in ILCs. RAG1-deficient mice given poly I:C exhibited increased frequency of TNF-α but not IFN-γ/IL17A-producing ILCs in the gut and depletion of ILCs prevented the poly I:C-driven intestinal damage. Our data indicate that CD-related inflammation is marked by accumulation of ILCs producing TNF-α and IFN-γ in the mucosa. Moreover, ILCs express TLR3 and are functionally able to respond to poly I:C with increased synthesis of TNF-α thus contributing to small intestinal atrophy.
Highlights
Celiac disease (CD) is a chronic enteropathy caused by dietary gluten in wheat, barley, and rye [1]
Several HLA-DQ2- and HLA-DQ8-restricted gluten peptides can promote the synthesis of interferon (IFN)-γ and interleukin (IL)-21 by CD4+ T cells [3, 4], while peptides p31-43 or p3149 from α-gliadin stimulate innate immune cells to produce IL-15, a cytokine involved in the activation of cytotoxic cells [i.e. natural killer (NK) cells and CD8+ T cells]
Innate lymphoid cells (ILCs) producing pro-inflammatory cytokines are significantly increased in the inflamed mucosa of active celiac disease patients
Summary
Celiac disease (CD) is a chronic enteropathy caused by dietary gluten in wheat, barley, and rye [1]. 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 [1, 2]. Recent studies have shown that wheat contains α-amilase/trypsin inhibitor (ATI) family members, a class of non-gluten proteins that interact with TLR4 and stimulate macrophages and dendritic cells to produce inflammatory cytokines [9]. Studies in mice that lack a functional adaptive immune response have shown that ILCs-derived IFNγ is a potent inducer of bacteria-driven acute and chronic colitis [19], confirming the pathogenic role of ILCs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
