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  • Interplay between Liver X Receptor and Hypoxia Inducible Factor 1α Potentiates Interleukin-1β Production in Human Macrophages.

Interplay between Liver X Receptor and Hypoxia Inducible Factor 1α Potentiates Interleukin-1β Production in Human Macrophages.

Cell reports (2020-05-21)
Louise Ménégaut, Charles Thomas, Antoine Jalil, Jean Baptiste Julla, Charlène Magnani, Adam Ceroi, Louise Basmaciyan, Adélie Dumont, Wilfried Le Goff, Mano Joseph Mathew, Cédric Rébé, Valentin Dérangère, Aline Laubriet, Valentin Crespy, Jean-Paul Pais de Barros, Eric Steinmetz, Nicolas Venteclef, Philippe Saas, Laurent Lagrost, David Masson
RESUMEN

Low-grade inflammation is constitutive of atherosclerosis, and anti-inflammatory therapy inhibiting interleukin-1β (IL-1β) reduces the rate of cardiovascular events. While cholesterol accumulation in atheroma plaque and macrophages is a major driver of the inflammatory process, the role of the LXR cholesterol sensors remains to be clarified. Murine and human macrophages were treated with LXR agonists for 48 h before Toll-like receptor (TLR) stimulation. Unexpectedly, we observe that, among other cytokines, LXR agonists selectively increase IL1B mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by activation of HIF-1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis. Treatment of human macrophages with carotid plaque homogenates also leads to induction of IL1B in an LXR-dependent manner. Thus, our work discloses a mechanism by which cholesterol and oxysterols trigger inflammation in atherosclerosis. This suggests perspectives to target IL-1β production in atherosclerotic patients.

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