[PDF][PDF] Lanosterol modulates TLR4-mediated innate immune responses in macrophages

E Araldi, M Fernández-Fuertes, A Canfrán-Duque… - Cell reports, 2017 - cell.com
E Araldi, M Fernández-Fuertes, A Canfrán-Duque, W Tang, GW Cline, J Madrigal-Matute
Cell reports, 2017cell.com
Macrophages perform critical functions in both innate immunity and cholesterol metabolism.
Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes
lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to
accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1
(HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of
Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with …
Summary
Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNβ-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity.
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