p31-43 Gliadin Peptide Forms Oligomers and Induces NLRP3 Inflammasome/Caspase 1- Dependent Mucosal Damage in Small Intestine

HERRERA, MARÍA GEORGINA; PRIETO, EDUARDO DANIEL; CARASI, PAULA; MICULÁN, EMANUEL; PEREZ, FEDERICO; PANTANO, SERGIO; GÓMEZ CASTRO, MARÍA FLORENCIA; RUERA, CAROLINA; BARRERA, EXEQUIEL; CHIRDO, FERNANDO GABRIEL; HERRERA, MARÍA GEORGINA; PRIETO, EDUARDO DANIEL; CARASI, PAULA; MICULÁN, EMANUEL; PEREZ, FEDERICO; PANTANO, SERGIO; GÓMEZ CASTRO, MARÍA FLORENCIA; RUERA, CAROLINA; BARRERA, EXEQUIEL; CHIRDO, FERNANDO GABRIEL

Frontiers in Immunology

Frontiers in Immunology

Año: 2019 vol. 10

Celiac disease (CD) is a chronic enteropathy elicited by a Th1 response to glutenpeptides in the small intestine of genetically susceptible individuals. However, it remainsunclear what drives the induction of inflammatory responses of this kind against harmlessantigens in food. In a recent work, we have shown that the p31-43 peptide (p31-43)from α-gliadin can induce an innate immune response in the intestine and that this mayinitiate pathological adaptive immunity. The receptors and mechanisms responsible forthe induction of innate immunity by p31-43 are unknown and here we present evidencethat this may reflect conformational changes in the peptide that allow it to activatethe NLRP3 inflammasome. Administration of p31-43, but not scrambled or invertedpeptides, to normal mice induced enteropathy in the proximal small intestine, associatedwith increased production of type I interferon and mature IL-1β. P31-43 showed asequence-specific spontaneous ability to form structured oligomers and aggregatesin vitro and induced activation of the ASC speck complex. In parallel, the enteropathyinduced by p31-43 in vivo did not occur in the absence of NLRP3 or caspase 1 andwas inhibited by administration of the caspase 1 inhibitor Ac-YVAD-cmk. Collectively,these findings show that p31-43 gliadin has an intrinsic propensity to form oligomerswhich trigger the NLRP3 inflammasome and that this pathway is required for intestinalinflammation and pathology when p31-43 is administered orally to mice. This innateactivation of the inflammasome may have important implications in the initial stages ofCD pathogenesis