The farnesoid X receptor regulates the development and function of monocyte/macrophage in inflammation and infection

As a nuclear receptor for bile acid, Farnesoid X receptor (FXR) is one of the key transcription factorsknown to regulate immune cell development and function. By regulating genes involved in manysignaling pathways, FXR is emerging as an attractive drug target for many inflammatory and infectiousdiseases. However, the molecular mechanism underlying FXR mediated regulation remains elusive. Inthis study, utilizing FXR-/-mice and multiple in vitro assays, we investigated the role of FXR in thedevelopment and function of monocyte/macrophage lineage. We found the ablation of FXR in miceleads to a defective monocyte/macrophage proliferation in bone marrow, which associated withdecreased expression of c-Fos-CREB via dephosphorylation of MAPK proteins Erk/p38/JNK.Intriguingly, we further noted that in cells treated with lipopolysaccharide in vitro, BMDM from FXR-/-mice expressed lower anti-inflammatory cytokine IL-10, but a comparable level of pro-inflammationcytokines, such as IL-1β, IL-6, and TNF-αcomparing to BMDM from WT littermates. Moreover, BMDMfrom FXR-/- mice displayed elevated NO production and accumulated more LPS-induced inducibleNitric oxide synthase (iNOS), which potentially promotes inflammation in vivo. Monocytes are essentialin host defense to Listeria infection. We further found decreased liver and spleen CFU in FXR-/-micecomparing to the WT littermates in L.monocytogene infection, which may through the contribution ofenhanced antibacterial function from monocytes as well as reduced monocytes as a reservoir forListeria. Together, we for the first time found that FXR regulates the development and function ofmonocyte/macrophage in inflammation and infection.