Rab guanine nucleotide exchange factor 1 (Rabgef1) restricts intestinal inflammation by limiting pro-inflammatory signals in Intestinal Epithelial Cells (IECs)

Abstract

Rab guanine nucleotide exchange factor (GEF-)1 (Rabgef1), a multifunctional protein whose in vivo functions remained unknown until recently, is highly expressed in mouse and human epithelial cells. The aim of this study is to investigate the role of Rabgef1 in intestinal epithelial cells (IECs) and intestinal homeostasis in mice. We performed conditional deletion of Rabgef1 gene using the cre-lox system to obtain mice lacking Rabgef1 specifically in IECs (Rabgef1IEC-KO), under the wild-type (WT) or the colitis-prone Interleukin-10 (Il-10)-deficient background. In addition, we used the CRISPR-Cas9 technology to obtain a murine IEC line deficient in Rabgef1. Rabgef1IEC-KO mice under the WT background did not develop spontaneous intestinal abnormalities but exhibited an altered intestinal microbial composition associated with minor changes in IEC pro-inflammatory gene expression profile. Moreover, Rabgef1IEC-KO mice exhibited an increased susceptibility to inflammation in a dextran sodium sulfate (DSS)-induced model of colitis under the WT background, as well as in a constitutive model of colitis under the Il-10-¬deficient background. In vitro, we showed that mouse IECs lacking Rabgef1 significantly overexpressed several pro-inflammatory cytokines and chemokines as compared to control cells. Taken together, these results support that Rabgef1 acts as a regulator of intestinal homeostasis and inflammation, and that dysregulated Rabgef1 expression could contribute to intestinal barrier dysfunction in inflammatory conditions of the gut