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

Abstract

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