Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages

Elisa Araldi, Marta Fernández-Fuertes, Alberto Canfrán-Duque, Wenwen Tang, Gary W. Cline, Julio Madrigal-Matute, Jordan S. Pober, Miguel A. Lasunción, Dianqing Wu, Carlos Fernández-Hernando, Yajaira Suárez

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2743-2755
Number of pages13
JournalCell Reports
Volume19
Issue number13
DOIs
StatePublished - Jun 27 2017

Keywords

  • Cyp51A1
  • innate immunity
  • lanosterol
  • macrophage
  • TLR4

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Araldi, E., Fernández-Fuertes, M., Canfrán-Duque, A., Tang, W., Cline, G. W., Madrigal-Matute, J., Pober, J. S., Lasunción, M. A., Wu, D., Fernández-Hernando, C., & Suárez, Y. (2017). Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. Cell Reports, 19(13), 2743-2755. https://doi.org/10.1016/j.celrep.2017.05.093