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Cell Rep. 2017 Jun 27;19(13):2743-2755. doi: 10.1016/j.celrep.2017.05.093.

Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages.

Author information

1
Department of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA; Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid y CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 28029 Madrid, Spain.
4
Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
6
Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
7
Department of Immunobiology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
8
Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid y CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 28029 Madrid, Spain.
9
Department of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: carlos.fernandez@yale.edu.
10
Department of Comparative Medicine, Department of Pathology, Program in Integrative Cell Signaling and Neurobiology of Metabolism and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: yajaira.suarez@yale.edu.

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.

KEYWORDS:

Cyp51A1; TLR4; innate immunity; lanosterol; macrophage

PMID:
28658622
PMCID:
PMC5553565
DOI:
10.1016/j.celrep.2017.05.093
[Indexed for MEDLINE]
Free PMC Article

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