AUTHOR=González de la Aleja Arturo , Herrero Cristina , Torres-Torresano Mónica , de la Rosa Juan Vladimir , Alonso Bárbara , Capa-Sardón Enrique , Muller Ittai B. , Jansen Gerrit , Puig-Kröger Amaya , Vega Miguel A. , Castrillo Antonio , Corbí Ángel L. TITLE=Activation of LXR Nuclear Receptors Impairs the Anti-Inflammatory Gene and Functional Profile of M-CSF-Dependent Human Monocyte-Derived Macrophages JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.835478 DOI=10.3389/fimmu.2022.835478 ISSN=1664-3224 ABSTRACT=

Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions but their contribution to human macrophage polarization remains unclear. The LXR pathway is enriched in pro-inflammatory macrophages from rheumatoid arthritis as well as in tumors-associated macrophages from human tumors. We now report that LXR activation inhibits the anti-inflammatory gene and functional profile of M-CSF-dependent human macrophages, and prompts the acquisition of a pro-inflammatory gene signature, with both effects being blocked by an LXR inverse agonist. Mechanistically, the LXR-stimulated macrophage polarization shift correlates with diminished expression of MAFB and MAF, which govern the macrophage anti-inflammatory profile, and with enhanced release of activin A. Indeed, LXR activation impaired macrophage polarization in response to tumor-derived ascitic fluids, as well as the expression of MAF- and MAFB-dependent genes. Our results demonstrate that LXR activation limits the anti-inflammatory human macrophage polarization and prompts the acquisition of an inflammatory transcriptional and functional profile.