title: Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota.
abstract: Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development.
authors.affiliation: State Key Laboratory of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition and School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue Wuxi, 214122 Jiangsu, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1163, Institut Imagine, 24 Boulevard du Montparnasse, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France.
authors.forename: Ramine
authors.initials: R
authors.lastname: Mecheri
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
authors.forename: Anne M
authors.initials: AM
authors.lastname: van der Does
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lundeberg
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1151, Institut Necker-Enfants Malades (INEM), Centre National de la Recherche Scientifique, Unité 8253, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Loredana
authors.initials: L
authors.lastname: Saveanu
authors.affiliation: State Key Laboratory of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition and School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue Wuxi, 214122 Jiangsu, P.R. China.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1151, Institut Necker-Enfants Malades (INEM), Centre National de la Recherche Scientifique, Unité 8253, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.affiliation: Medical Microbial Pathogenesis Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1151, Institut Necker-Enfants Malades (INEM), Centre National de la Recherche Scientifique, Unité 8253, 149 rue de Sèvres, 75015 Paris, France. Electronic address: julien.diana@inserm.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Diana
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000382:microbiology; D005232:Fatty Acids, Volatile / Q000276:immunology; D005260:Female; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D064307:Microbiota / Q000502:physiology*; D010179:Pancreas / Q000276:immunology* / Q000382:microbiology
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D005232:Fatty Acids, Volatile