title: TNF-α Producing Innate Lymphoid Cells (ILCs) Are Increased in Active Celiac Disease and Contribute to Promote Intestinal Atrophy in Mice.
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.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Marafini
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Di Fusco
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Cupi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Omero Alessandro
authors.initials: OA
authors.lastname: Paoluzi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Colantoni
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Ortenzi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Izzo
authors.affiliation: Department of Surgery, San Pietro Fatebenefratelli hospital, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Vita
authors.affiliation: Department of Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: De Luca
authors.affiliation: Department of Surgery, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sica
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001284:Atrophy / Q000276:immunology / Q000473:pathology; D002446:Celiac Disease / Q000276:immunology / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D011070:Poly I-C / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C