title: Mechanisms of innate immune activation by gluten peptide p31-43 in mice.
abstract: Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Innate immunity contributes to the pathogenesis of CD, but the mechanisms remain poorly understood. Although previous in vitro work suggests that gliadin peptide p31-43 acts as an innate immune trigger, the underlying pathways are unclear and have not been explored in vivo. Here we show that intraluminal delivery of p31-43 induces morphological changes in the small intestinal mucosa of normal mice consistent with those seen in CD, including increased cell death and expression of inflammatory mediators. The effects of p31-43 were dependent on MyD88 and type I IFNs, but not Toll-like receptor 4 (TLR4), and were enhanced by coadministration of the TLR3 agonist polyinosinic:polycytidylic acid. Together, these results indicate that gliadin peptide p31-43 activates the innate immune pathways in vivo, such as IFN-dependent inflammation, relevant to CD. Our findings also suggest a common mechanism for the potential interaction between dietary gluten and viral infections in the pathogenesis of CD.
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP)(CONICET-UNLP), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina;
authors.forename: Romina E
authors.initials: RE
authors.lastname: Araya
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP)(CONICET-UNLP), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina;
authors.forename: María Florencia
authors.initials: MF
authors.lastname: Gomez Castro
authors.affiliation: Catedra de Microbiología, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina;
authors.forename: Paula
authors.initials: P
authors.lastname: Carasi
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada;
authors.forename: Justin L
authors.initials: JL
authors.lastname: McCarville
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jury
authors.affiliation: Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Mowat
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada;
authors.forename: Elena F
authors.initials: EF
authors.lastname: Verdu
authors.affiliation: Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP)(CONICET-UNLP), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina; fchirdo@gmail.com.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Chirdo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002446:Celiac Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005838:Genotype; D005903:Gliadin / Q000008:administration & dosage / Q000633:toxicity*; D007113:Immunity, Innate / Q000187:drug effects*; D018928:Immunity, Mucosal / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D007370:Interferon Type I; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010446:Peptide Fragments; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; C549457:gliadin p31-43; D053633:Receptor, Interferon alpha-beta; D005903:Gliadin; D011070:Poly I-C
keywords: celiac disease; innate immunity; p31-43; polyinosinic:polycytidylic acid; small intestine