Abstract 502: Aldo-keto reductase 1B8 (AKR1B8) deficiency causes intestinal immune deficiency

Abstract

Abstract Background: Intestinal epithelial cells (IECs) are crucial mediators of intestinal immunity. IECs defects may disrupt development and maturation of intestinal immunity. Aldo-keto reductase 1B10 (AKR1B10) is a regulator of de novo fatty acids synthesis and lipid synthesis by mediating acetyl-CoA carboxylase-α (ACCA) stability. Aldo-keto reductase 1B8 (AKR1B8) is an ortholog in mice of human AKR1B10, which has similar regulatory function in fatty acid/lipid synthesis. AKR1B8 deficiency causes IECs defects in proliferation and self-renewal, which may lead to dysregulation of intestinal immunity. Methods: AKR1B8 -/- mice mouse stain was produced by homozygous recombination. Immune cells were isolated from colonic lamina propria (cLP) and mesenteric lymph nodes (MLN). Flow cytometry and immunofluorescence staining were applied for immune cell sorting and measurements. Microbiota composition were quantified by next generation sequencing. Results: AKR1B8 deficiency causes infiltration of neutrophils, mast cells and basophils in the colon. Also, AKR1B8 deficiency causes impaired γδT cells and T helper cells (Th cells) immunity, such as IFNγ, IL17, IL4 or IL22 production, in colon and mesenteric lymph nodes, while enhances distinct arm of CD8 activity and Treg cells. These alterations may be due to the changes of MHCII+ DCs and CD103+ DCs in AKR1B8 deficient mice. Meanwhile, AKR1B8 inhibits the phosphorylation of p-AKT (T308 and S473) and p-ERK (1/2) in IECs, and suppresses the regulation IKKα/NF-κB signaling cascades. Furthermore, AKR1B8 deficiency induces gut microbiota shifts with higher ratio of Firmicutes/Bacteroidetes. Conclusions: AKR1B8 is a critical mediators for IECs signaling and immune homeostasis. Loss of AKR1B8 in IECs induces Th cells immune deficiency. This study identified a new compensatory mechanism under IECs defects for maintaining intestinal immune homeostasis. Citation Format: Xin Wang, Deliang Cao. Aldo-keto reductase 1B8 (AKR1B8) deficiency causes intestinal immune deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 502.