The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Abstract

The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR−/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

SUMOylation of the Farnesoid X Receptor (FXR) Regulates the Expression of FXR Target Genes

“…Vavassori and associates (30) recently reported that SUMOylation of FXR only at Lys 277 in HEK293 cells was required for FXR-mediated trans-repression of cytokine expression induced by the FXR ligand INT-747. This suggests that there may be tissue-specific differences in the numbers of SUMOylation sites important for regulating expression of FXR target genes.…”

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

“…Mice treated with a FXR agonist were shown to be protected against chemically induced colitis (Gadaleta et al, 2011b), which permits the hypothesis that FXR activation inhibits inflammation. Vavassori et al (2009) showed that, as a component of a network of nuclear receptors, FXR regulates intestinal innate immunity and homeostasis. In vitro assays show that intestinal inflammation strongly reduces FXR activation (Gadaleta et al, 2011a).…”

Bile Acid Receptor Activation Modulates Hepatic Monocyte Activity and Improves Nonalcoholic Fatty Liver Disease

“…The demonstration that mice knocked out for both the LDL receptor and FXR and fed a high-fat diet develop necroinflammation and greater hepatic levels of proinflammatory cytokines, TGF␤, procollagen, and collagen compared with LDL receptor Ϫ/Ϫ /FXR ϩ/ϩ mice implicates a role for FXR in determining the features typical of NASH (15). Furthermore, FXR exerts homoeostatic functions at the interface between nutrient and lipid metabolism with innate immunity, antagonizing NF-B in hepatic inflammatory responses (17) and inhibiting intestinal inflammatory responses (16,18).…”