Activation of IL-17/CEBPB/PFKFB3 triggers energy metabolic switching and goblet cell differentiation in ulcerative colitis.

Goblet cell depletion, frequently reported as a symptom of ulcerative colitis (UC), may reflect a combination of increased mucus release, decreased mucus storage, and altered goblet cell differentiation. Here, we studied the underlying mechanisms of CCAAT/enhancer-binding protein beta (CEBPB), which is enriched in interleukin (IL)-17 signaling, in goblet cell differentiation during UC. The IL-17/CEBPB/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) signaling axis in vivo was elicited through an IL-17A-neutralizing antibody and adeno-associated viruses targeting goblet cells. Goblet cells were used to assess the effects of IL-17/CEBPB/PFKFB3 signaling on goblet cell differentiation. IL-17 signaling activated CEBPB-mediated PFKFB3 transcription in goblet cells of dextran sodium sulfate-induced mice and drove a switch in the mode of energy metabolism from oxidative phosphorylation to aerobic glycolysis in goblet cells. The abnormal glycolytic activity of goblet cells was detrimental to cell differentiation and maturation, leading to decreased mucin secretion and weakened intestinal barrier capacity of the goblet cells, which led to the progression of UC. Overall, these results indicate that IL-17 pro-inflammatory signaling activates CEBPB/PFKFB3 expression to drive aerobic glycolysis in goblet cells, leading to goblet cell dysfunction and UC progression.