title: Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+phenotype.
abstract: Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire an IL-10+ phenotype upon interaction with FoxP3+ Treg cells, MCs of NOD mice do not undergo this tolerogenic differentiation. Our data indicate that overly inflammatory MCs unable to acquire a tolerogenic IL-10+ phenotype contribute to the pathogenesis of autoimmune T1D.
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Betto
authors.affiliation: Experimental Diabetes Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vera
authors.initials: V
authors.lastname: Usuelli
authors.affiliation: Experimental Diabetes Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mandelli
authors.affiliation: Mediterranean Institute for Transplantation and Advanced Specialized Therapies, ISMETT, Palermo, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Badami
authors.affiliation: Experimental Diabetes Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sorini
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Capolla
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Danelli
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Frossi
authors.affiliation: Department of Human Pathology, University of Palermo, Palermo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarnotta
authors.affiliation: Department of Human Pathology, University of Palermo, Palermo, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ingrao
authors.affiliation: Department of Human Pathology, University of Palermo, Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy. Electronic address: cpucillo@gmail.com.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pucillo
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gri
authors.affiliation: Department of Biomedical Science and Technology and M.A.T.I. Center of Excellence, University of Udine, Udine, Italy. Electronic address: falcone.marika@hsr.it.
authors.forename: Marika
authors.initials: M
authors.lastname: Falcone
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001786:Blood Glucose / Q000378:metabolism; D053818:Chymases / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D007249:Inflammation; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D061346:Laser Capture Microdissection; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology
chemical_list: D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; C577686:interleukin-6, mouse; D016753:Interleukin-10; C509227:Cma1 protein, mouse; D053818:Chymases
keywords: Autoimmune diabetes; Immune tolerance; Interleukin-10; Interleukin-6; Mast cells