TY - JOUR
T1 - Activation of LXR Nuclear Receptors Impairs the Anti-Inflammatory Gene and Functional Profile of M-CSF-Dependent Human Monocyte-Derived Macrophages
AU - González de la Aleja, Arturo
AU - Herrero, Cristina
AU - Torres-Torresano, M. nica
AU - de la Rosa, Juan Vladimir
AU - Alonso, B. rbara
AU - Capa-Sardón, Enrique
AU - Muller, Ittai B.
AU - Jansen, Gerrit
AU - Puig-Kröger, Amaya
AU - Vega, Miguel A.
AU - Castrillo, Antonio
AU - Corbí, Ángel L.
N1 - Funding Information: This work was supported by grants from Ministerio de Ciencia, Investigación y Universidades (SAF2017-83785-R to MV and ALC), Ministerio de Ciencia, Investigación 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. Publisher Copyright: Copyright © 2022 González de la Aleja, Herrero, Torres-Torresano, de la Rosa, Alonso, Capa-Sardón, Muller, Jansen, Puig-Kröger, Vega, Castrillo and Corbí.
PY - 2022/2/24
Y1 - 2022/2/24
N2 - 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.
AB - 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.
KW - LXR
KW - inflammation
KW - innate immunity
KW - macrophage
KW - macrophage polarization
UR - http://www.scopus.com/inward/record.url?scp=85126241482&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2022.835478
DO - https://doi.org/10.3389/fimmu.2022.835478
M3 - Article
C2 - 35280993
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 835478
ER -