Activation of LXR nuclear receptors impairs the anti-inflammatory gene and functional profile of M-CSF-dependent human monocyte-derived macrophages

13 p.-7 fig.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.This work was supported by grants from Ministerio de Ciencia, Investigación y Universidades (SAF2017-83785-R to MV and ALC), Ministerio de Ciencia, Innovación y Universidades y Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017-90604-REDT and PID2019-104284RB-I00/AEI/10.13039/501100011033 to AC), Fundación La Marató/TV3 (Grant 201619.31 to ALC), Instituto de Salud Carlos III (Grant PI20/00316 to AP-K), and Red de Investigación en Enfermedades Reumáticas (RIER, RD16/0012/0007) from Instituto de Salud Carlos III and cofinanced by the European Regional Development Fund “A way to achieve Europe” (ERDF) to AP-K and ALC. This work was also supported in part by a grant from the Dutch Society for Clinical Chemistry (NVKC) to IM and R. de Jonge. AGA was funded by FPU predoctoral fellowship (FPU16/02756) from Ministerio de Universidades.Peer reviewe