AIM2 Promotes Epithelial Tuft Cell Development During Intestinal Type 2 Immune Responses

Abstract The epithelium performs a growing list of immunologically relevant functions at mucosal sites. Specialized epithelial cells the intestine interact with microbiota and lamina propria immune to regulate host defense, yet we know little about molecular regulators linking these interactions during different immunological insults. Here, found that DNA sensor Absent in Melanoma 2 (AIM2) promotes development tuft cells, which initiate intestinal type immunity. Aim2-deficient organoids displayed reduced cell gene signatures numbers treatment cell-promoting cytokines IL-4 IL-13. Tuft respond microbial metabolite succinate, leading IL-13 production by innate lymphoid (ILC2s) hyperplasia vivo. Succinate-fed Aim2 −/−mice IL13 expression compared similarly treated wild mice. Inflammasome-deficient Asc mice similar succinate-induced profiles, suggesting AIM2 cell-ILC2 activation independently its inflammasome function. RNA sequencing revealed −/−intestinal diminished O-linked N-acetylglucosamine transferase (OGT), is required for IL13/STAT6-induced expansion. In line findings, succinate-treated presented OGT protein STAT6 phosphorylation. These combined results reveal an novel role inflammation via promotion expansion, potentially through maintaining OGT-STAT6 signaling. Supported grants from NIH (K22 CA212030) AZ Dept. Health Services (AZBRC New Investigator Award).