Role of the inflammasome in the small intestinal damage

CAROLINA N. RUERA; MICULÁN, EMANUEL GONZALO; DUCCA, GERÓNIMO; FEDERICO PEREZ; IRIBARREN MARÍA LUZ; CARASI, PAULA; CHIRDO FERNANDO

Congreso; 13th Latin American and Caribbean Immunology- ALACI22; 2022

ALACI

Celiac disease (CD) is a chronic enteropathy elicited by a Th1 response to gluten peptides in the small intestine of genetically susceptible individuals. However, it remains unclear what drives the induction of inflammatory responses against harmless antigens in food, such as gluten peptides. To assess the inflammatory response in the small intestine, we developed an experimental model in wild-type mice by intragastric administration of a single dose of p31-43 (a 13mer synthetic gluten peptide). By biophysical and molecular dynamics, we showed that p31-43 forms stable oligomers, and in vivo studies demonstrated that mucosal damage triggered by p31-43 requires the NLRP3 inflammasome (NLRP3, ASC, and caspase-1). To assess the role of the inflammasome in the mucosal damage, inhibitors for NLRP3 (MCC950), Ac-YVAD-cmk (caspase-1), and blockade by neutralizing anti-IL-1b antibody were evaluated. We found that histological changes in the proximal small intestine assessed by reduction of Villus height/Crypt depth ratio, and increase in IEL number induced by p31-43, were abolished by specific inhibition of caspase-1 or NLRP3. While antibody-mediated blocking of IL-1β did not alter the inflammasome activation, inhibited both the histological changes and the induction of apoptosis and caspase-3 activation driven by p31-43. These findings highlight the role of the inflammasome and particularly, IL-1β in mucosal damage in a model of sterile inflammation. This may help to explain the molecular pathogenesis in the induction of pro-inflammatory effects and subsequent damage to the intestinal mucosa in chronic inflammatory conditions in the gut.