Immunomodulatory functions of FXR

Abstract

The Farnesoid-x-receptor (FXR) is a bile acids sensor activated in humans by primary bile acids. FXR is mostly expressed in liver, intestine and adrenal glands but also by cells of innate immunity, including macrophages, liver resident macrophages, the Kupffer cells, natural killer cells and dendritic cells. In normal physiology and clinical disorders, cells of innate immunity mediate communications between liver, intestine and adipose tissues. In addition to FXR, the G protein coupled receptor (GPBAR1), that is mainly activated by secondary bile acids, whose expression largely overlaps FXR, modulates chemical communications from the intestinal microbiota and the host's immune system, integrating epithelial cells and immune cells in the entero-hepatic system, providing a mechanism for development of a tolerogenic state toward the intestinal microbiota. Disruption of FXR results in generalized inflammation and disrupted bile acids metabolism. While FXR agonism in preclinical models provides counter-regulatory signals that attenuate inflammation-driven immune dysfunction in a variety of liver and intestinal disease models, the clinical relevance of these mechanisms in the setting of FXR-related disorders remain poorly defined.

Keywords: Farnesoid-x-receptor; G protein coupled receptor 1; Hepatic macrophages; Immune regulation; Intestinal microbiota; Non alcoholic steatohepatitis (NASH).