iTie controls intestinal tolerance through suppressing the NLRP6 inflammasome

Abstract

Intestines are full of commensal bacteria that possess numerous pathogen-associated molecular patterns. How the intestinal epithelial cells are tolerant to these stimuli under normal conditions is still elusive. Here we show that iTie is expressed in small intestinal enterocytes and its deficiency leads to body weight loss in mice, accompanied by length reduce of small intestines and intestinal villi. The activation of NLRP6 inflammasome is exacerbated upon iTie deletion. iTie has a higher binding affinity for NLRP6 than NLRP6s physiological ligand LTA does. iTie deficiency gives rise to uncontrolled GSDMD activation and pyroptosis of small intestinal enterocytes. Inhibition of GSDMD permeabilization on cell membrane ameliorates the damage caused by iTie deficiency. iTes expression is diminished in small intestines of patients with Crohns disease. Our results uncover a self-control system for mouse intestine to tolerate commensal bacteria which might shed new light on the treatment of bowel diseases.