Compartmentalization of Toll-like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a, a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell-intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild-type controls, germ-free Rab11a-deficient mouse intestines failed to tolerate the intraluminal stimulation of microbial agonists. Thus, Rab11a endosome controls intestinal host-microbial homeostasis at least partially via sorting TLRs.
Immunologic tolerance to intestinal microbiota depends on Rab11 endosome-mediated control of pathogen pattern recognition receptor TLR9 processing and signaling.
- Loss of Rab11a in enterocytes causes cell-autonomous inflammatory cytokine production and crypt cell proliferation.
- Rab11a endosomes control Toll-like receptor distribution and processing in intestinal epithelial cells.
- Rab11a endosome-mediated host–microbial homeostasis is conserved in flies and mammals.