Gene expression in the AhR activation pathway and Arthritis susceptibility in mice

Abstract

Autoimmune diseases such as rheumatoid arthritis are increasingly associated with alterations in intestinal microbiota. The microbiota also regulates fundamental aspects of the immune system, and several molecules have been described as bridges connecting the microbial environment and the host. One of these molecules is the AhR (aryl hydrocarbon receptor) a receptor and transcription factor capable of responding to an array of endogenous and exogenous ligands (environmental, diet-related and microbial). AhR activation regulates T and B cell differentiation, as well as the metabolization of compounds with carcinogenic potential. In the pristane-induced arthritis model (PIA), which recapitulates many aspects of the human disease, mouse strains developed in our laboratory show extremely divergent susceptibility, such as the HIII (resistant) and LIII (extremely susceptible) strains. These mice harbor distinct intestinal microbiotas and transfer of newborn pups to foster mothers of the opposite strain (cross-fostering) partially transferred the susceptibility/resistance phenotypes. HIII and LIII mice carry distinct AhR alleles, and two important genes in the AhR activation pathway (Arnt and Ahrr) map to the confidence interval of PIA susceptibility regulatory QTL (quantitative trait loci). These results suggest that the expression of genes in the AhR activation pathway may modulate the immune response to microbiota-derived stimuli, modulating PIA development in distinct ways in HIII and LIII strains. We will investigate the expression of genes in the AhR activation pathway, aiming at identifying their correlation to PIA susceptibility and to microbiota parameters in cross-fostered and non-cross-fostered HIII and LIII mice. (AU)