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,Antonio Castrillo,Ángel L Corbí,Mónica Torres-Torresano,Ittai B Muller,Amaya Puig-Kröger,Enrique Capa-Sardón,Gerrit Jansen,Cristina Herrero,Bárbara Alonso,Miguel A Vega,Juan Vladimir De La Rosa

doi:10.3389/fimmu.2022.835478

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.

Highlights

Macrophages defend the organism against endogenous danger signals and exogenous threats, and initiate and resolve inflammatory responses
We report that Liver X Receptors (LXR) activation impairs the acquisition of the transcriptional and functional properties of anti-inflammatory M-MØ and Tumor-derived Ascitic Fluid (TAF)-MØ, and inhibits the expression of the transcription factors (MAF, MAFB) that shape the gene and functional profile of M-CSFdependent macrophages
The transcriptome of M-MØ shows a very strong enrichment of genes preferentially expressed by large tumorassociated macrophages (Figure 1B), whose presence associates with a lower disease-free survival rate in colorectal liver metastasis [42], while the transcriptome of GMMØ resembles the specific gene profile of “small TAM” [42] and rheumatoid arthritis synovial fluid macrophages (RASF-MØ) [53] (Figure 1B)

Summary

Introduction

Macrophages defend the organism against endogenous danger signals and exogenous threats, and initiate and resolve inflammatory responses. To perform these tasks, macrophages can display a huge spectrum of activation (“polarization”) states, whose acquisition depends on their. M-CSF is indispensable for tissue-resident and monocyte-derived macrophage differentiation [6–9], and primes macrophages (M-MØ) for acquisition of an anti-inflammatory and immunosuppressive profile (IL10high TNFlow IL23low IL6low) [5, 10–19]. M-MØ resemble tissue-resident ‘trophic’ macrophages, whereas GM-MØ represent proinflammatory monocyte-derived macrophages In line with their effector functions, M-MØ and GM-MØ exhibit distinct transcriptional profiles [10, 13, 20–22] that resemble those of human resident and inflammatory macrophages in vivo [20, 23– 25], and differ in their responsiveness to the immunosuppressant drug methotrexate (MTX) [26, 27]

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Results

Conclusion