P059 GSDMB triggers intestinal inflammation via regulating BHLHA15-mediated hyperactive unfolded protein response

Abstract

Abstract Background Impaired intestinal epithelial barrier has been considered to be associated with an increasing variety of gastrointestinal diseases, especially inflammatory bowel disease (IBD) encompassing Crohn’s disease (CD) and ulcerative colitis (UC). Herein, we investigated the role of Gasdermin B (GSDMB) in modulating intestinal epithelial barrier integrity and proposed a promising therapeutic strategy. Methods We generated GSDMB (GSDMBfl/fl;Villin-Cre) intestinal epithelial-specific knock in mice to observe the functions of GSDMB in intestinal epithelial barrier. RNA-seq analysis and human and murine intestine-derived organoids were used to determine the mechanism of function of GSDMB. Results To interrogate the intestinal functions of GSDMB in vivo, we generated GSDMB conditional knock in mice (heterozygote: GSDMBfl/-;Villin-Cre; homozygote: GSDMBfl/fl;Villin-Cre) by crossing a mouse line containing the floxed alleles of human GSDMB and a transcriptional stop codon at the transcriptional initiation site (GSDMBfl/fl) with the mouse line expressing Cre-recombinase under control of the Villin promoter (Villin-Cre). GSDMBfl/fl;Villin-Cre mice developed spontaneous enterocolitis and exhibited aberrant intestinal barrier integrity (as shown in the figure). GSDMB prominently provoked cell death of absorptive enterocytes and affected the function of goblet cells and Paneth cells in this setting. Mechanistically, epithelial GSDMB modulated hyperactive unfolded protein response of IECs by up-regulating BHLHA15 to mediate intestinal barrier injury instead of by the invasion of pathogenic microorganisms. Conclusion We have uncovered an important and a previously unrecognized role of GSDMB in intestinal inflammation, which represents a potential therapeutic target for IBD.