Toll-Like Receptors Induce Signal-Specific Reprogramming of the Macrophage Lipidome.

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Abstract

Macrophages reprogram their lipid metabolism in response to activation signals. However, a systems-level understanding of how different pro-inflammatory stimuli reshape the macrophage lipidome is lacking. Here, we use complementary "shotgun" and isotope tracer mass spectrometry approaches to define the changes in lipid biosynthesis, import, and composition of macrophages induced by various Toll-like receptors (TLRs) and inflammatory cytokines. "Shotgun" lipidomics data revealed that different TLRs and cytokines induce macrophages to acquire distinct lipidomes, indicating their specificity in reshaping lipid composition. Mechanistic studies showed that differential reprogramming of lipid composition is mediated by the opposing effects of MyD88- and TRIF-interferon-signaling pathways. Finally, we applied these insights to show that perturbing reprogramming of lipid composition can enhance inflammation and promote host defense to bacterial challenge. These studies provide a framework for understanding how inflammatory stimuli reprogram lipid composition of macrophages while providing a knowledge platform to exploit differential lipidomics to influence immunity.

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Journal

Journal ID (iso-abbrev): Cell Metab

Title: Cell metabolism

Publisher: Elsevier BV

ISSN (Electronic): 1932-7420

ISSN (Print): 1550-4131

Publication date (Electronic): Jul 07 2020

Volume: 32

Issue: 1

Affiliations

[1 ] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

[2 ] Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

[3 ] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA.

[4 ] Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

[5 ] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

[6 ] Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

[7 ] Department of Immunology, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA.

[8 ] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.

[9 ] Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA.

[10 ] Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: sbensinger@mednet.ucla.edu.

Article

Publisher Item ID: S1550-4131(20)30242-4

DOI: 10.1016/j.cmet.2020.05.003

PubMed ID: 32516576

SO-VID: 39032bb3-cb02-4742-8e89-0484123597ea

History

Keywords: toll-like receptors,stearoyl-CoA desaturase,stable isotope tracer analysis,macrophages,lipidomics,interferon,inflammation,host defense,acetylated-LDL,MyD88

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Keywords: toll-like receptors, stearoyl-CoA desaturase, stable isotope tracer analysis, macrophages, lipidomics, interferon, inflammation, host defense, acetylated-LDL, MyD88

Toll-Like Receptors Induce Signal-Specific Reprogramming of the Macrophage Lipidome.

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