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
Affiliations
Elisa Araldi
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
Marta Fernández-Fuertes
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
Alberto Canfrán-Duque
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
Wenwen Tang
Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA
Gary W. Cline
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
Julio Madrigal-Matute
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
Jordan S. Pober
Department of Immunobiology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA
Miguel A. Lasunción
Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid y CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 28029 Madrid, Spain
Dianqing Wu
Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA
Carlos Fernández-Hernando
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
Yajaira Suárez
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
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.
