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

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.

SUBMITTER: Gonzalez de la Aleja A

PROVIDER: S-EPMC8907538 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

González de la Aleja Arturo A Herrero Cristina C Torres-Torresano Mónica M de la Rosa Juan Vladimir JV Alonso Bárbara B Capa-Sardón Enrique E Muller Ittai B IB Jansen Gerrit G Puig-Kröger Amaya A Vega Miguel A MA Castrillo Antonio A Corbí Ángel L ÁL

Frontiers in immunology 20220224

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 s ...[more]

PMID: 35280993

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Project description:BackgroundDepression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses.MethodsOur goal was to characterize the pro-inflammatory profile of patients with MDD by measuring pro-inflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo.FindingOur results show that patients with MDD without other comorbidities (N = 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+CD16brightCD14neg) monocytes and increased activation state (CD40+CD86+) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Sub-anaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS.InterpretationOur results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.FundingThis study was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-FONCYT).

Dataset Information

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

Publications

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

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