Activation of LXR Nuclear Receptors Impairs the Anti-Inflammatory Gene and Functional Profile of M-CSF-Dependent Human Monocyte-Derived Macrophages

Arturo González de la Aleja, Cristina Herrero, M. nica Torres-Torresano, Juan Vladimir de la Rosa, B. rbara Alonso, Enrique Capa-Sardón, Ittai B. Muller, Gerrit Jansen, Amaya Puig-Kröger, Miguel A. Vega, Antonio Castrillo, Ángel L. Corbí

Research output: Contribution to journalArticle*Academicpeer-review

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.
Original languageEnglish
Article number835478
JournalFrontiers in immunology
Volume13
DOIs
Publication statusPublished - 24 Feb 2022

Keywords

  • LXR
  • inflammation
  • innate immunity
  • macrophage
  • macrophage polarization

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