Modulation of Intestinal Epithelial Tuft Cells by the Innate Immune Sensor, AIM2

Abstract

Chronic intestinal inflammation, the predominant characteristic of Inflammatory Bowel Diseases (IBD), can have serious long-term complications. Most notable is the promotion of tumorigenesis and colorectal cancer (CRC), or colitis associated cancer (CAC). Similarly, the development of small bowel cancer has also been attributed to chronic inflammation. In addition to environmental factors and genetic susceptibility, the inflammation associated with IBD can result from an intolerance to commensal organisms, which are recognized by pattern recognition receptors (PRRs). One of these PRRs, Absent In Melanoma 2 (AIM2), binds microbial- and host-derived dsDNA released into the cytosol, promoting formation of the multi-protein complex known as the inflammasome, in both epithelial and immune cells. AIM2-mediated cytokine release and signaling facilitates host defenses as well as intestinal epithelial cell (IEC) homeostasis. Additionally, AIM2 protects against aberrant activation of the PI3K and c-Myc pathways during CRC but has yet to be studied in small intestine inflammation induced cancer. This anti-tumorigenic response in the colon has been attributed to AIM2 expression in intestinal stem cells (ISCs), while other IEC populations have not been explored. Homeostasis in IEC populations require tightly coordinated equilibrium mediated by the constant shedding and self-renewing property of ISCs. Type 2 cytokine-secreting Tuft cells are IECs characterized by their expression of Doublecortin-Like Kinase 1 (DCLK1). Tuft cells can promote tissue repair, resolution of inflammation, and host defense against helminth infections. Although not fully understood, DCLK1 has also been proposed to mark a distinct cancer-associated stem cell population in the colon. However, the contribution of DCLK1 and Tuft cells during small bowel tumorigenesis is unknown. When examining markers of intestinal epithelium differentiation IEC cultures with Aim2 deletion repeatedly demonstrated diminished the Tuft cell marker, Dclk1. Administration of the microbial metabolite, succinate, which promotes Tuft cell expansion and type 2 cytokine production in the small intestine, failed to promote Dclk1 in Aim2-deficient small intestines, while having no impact on colonic expression irrespective of Aim2. Alternatively, mice with Aim2-deficiency specifically in the intestinal epithelium demonstrated a lack of Tuft cell response to succinate in the small intestine. Interestingly, Aim2 expression resulted in marked reduction of Tuft cell markers during type 1 DSS-colitis. Our findings suggest a differential role for AIM2 in regulating Dclk1 expression in IECs during alternative inflammatory stimuli.