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http://hdl.handle.net/10553/121744
Título: | Inhibition of LXR controls the polarization of human inflammatory macrophages through upregulation of MAFB | Autores/as: | González de la Aleja, Arturo Herrero, Cristina Torres-Torresano, Mónica Schiaffino, María Teresa del Castillo, Alejandro Alonso, Bárbara Vega, Miguel A. Puig-Kröger, Amaya Castrillo Viguera, Antonio Corbí, Ángel L. |
Clasificación UNESCO: | 32 Ciencias médicas 320509 Reumatología 2407 Biología celular |
Palabras clave: | Inflammation Innate Immunity Macrophage Polarization Transcriptional Profile |
Fecha de publicación: | 2023 | Publicación seriada: | Cellular and Molecular Life Sciences | Resumen: | Monocyte-derived macrophages contribute to pathogenesis in inflammatory diseases and their effector functions greatly depend on the prevailing extracellular milieu. Whereas M-CSF primes macrophages for acquisition of an anti-inflammatory profile, GM-CSF drives the generation of T cell-stimulatory and pro-inflammatory macrophages. Liver X Receptors (LXRα and LXRβ) are nuclear receptors that control cholesterol metabolism and regulate differentiation of tissue-resident macrophages. Macrophages from rheumatoid arthritis and other inflammatory pathologies exhibit an enriched LXR pathway, and recent reports have shown that LXR activation raises pro-inflammatory effects and impairs the acquisition of the anti-Inflammatory profile of M-CSF-dependent monocyte-derived macrophages (M-MØ). We now report that LXR inhibition prompts the acquisition of an anti-inflammatory gene and functional profile of macrophages generated within a pathological environment (synovial fluid from Rheumatoid Arthritis patients) as well as during the GM-CSF-dependent differentiation of human monocyte-derived macrophages (GM-MØ). Mechanistically, inhibition of LXR results in macrophages with higher expression of the v-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB) transcription factor, which governs the macrophage anti-inflammatory profile, as well as over-expression of MAFB-regulated genes. Indeed, gene silencing experiments on human macrophages evidenced that MAFB is required for the LXR inhibitor to enhance the anti-inflammatory nature of human macrophages. As a whole, our results demonstrate that LXR inhibition prompts the acquisition of an anti-inflammatory transcriptional and functional profile of human macrophages in a MAFB-dependent manner, and propose the use of LXR antagonists as potential therapeutic alternatives in macrophage re-programming strategies during inflammatory responses. | URI: | http://hdl.handle.net/10553/121744 | ISSN: | 1420-682X | DOI: | 10.1007/s00018-023-04745-4 | Fuente: | Cellular and Molecular Life Sciences [ISSN 1420-682X], v. 80 (4): 96, (Abril 2023) |
Colección: | Artículos |
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