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

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...

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Published in	Cell metabolism Vol. 32; no. 1; pp. 128 - 143.e5
Main Authors	Hsieh, Wei-Yuan, Zhou, Quan D., York, Autumn G., Williams, Kevin J., Scumpia, Philip O., Kronenberger, Eliza B., Hoi, Xen Ping, Su, Baolong, Chi, Xun, Bui, Viet L., Khialeeva, Elvira, Kaplan, Amber, Son, Young Min, Divakaruni, Ajit S., Sun, Jie, Smale, Stephen T., Flavell, Richard A., Bensinger, Steven J.
Format	Journal Article
Language	English
Published	United States Elsevier Inc 07.07.2020
Subjects	acetylated-LDL Animals Cell Line host defense inflammation interferon Lipidomics macrophages Macrophages - metabolism Male Mice Mice, Knockout Mice, Transgenic MyD88 Signal Transduction stable isotope tracer analysis stearoyl-CoA desaturase toll-like receptors Toll-Like Receptors - metabolism macrophages toll-like receptors stable isotope tracer analysis inflammation stearoyl-CoA desaturase host defense acetylated-LDL interferon MyD88 lipidomics
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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. [Display omitted] •A quantitative profiling of the mouse macrophage lipidome activated by immune stimuli•Macrophages alter lipid composition in a TLR-specific manner•MyD88-dependent TLRs alter lipid composition by increasing de novo MUFA synthesis•Inhibiting MUFA synthesis increases inflammation generated by MyD88-dependent TLRs Using a combination of shotgun lipidomics and stable-isotope tracing, Hsieh et al. show that distinct pro-inflammatory stimuli reshape the macrophage lipid composition in a signal-specific manner and that targeting this change can increase immunity. Thus, the study provides an in-depth resource and framework for understanding this lipidomic response while suggesting approaches for future therapy.
AbstractList	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. [Display omitted] •A quantitative profiling of the mouse macrophage lipidome activated by immune stimuli•Macrophages alter lipid composition in a TLR-specific manner•MyD88-dependent TLRs alter lipid composition by increasing de novo MUFA synthesis•Inhibiting MUFA synthesis increases inflammation generated by MyD88-dependent TLRs Using a combination of shotgun lipidomics and stable-isotope tracing, Hsieh et al. show that distinct pro-inflammatory stimuli reshape the macrophage lipid composition in a signal-specific manner and that targeting this change can increase immunity. Thus, the study provides an in-depth resource and framework for understanding this lipidomic response while suggesting approaches for future therapy. 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. 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. Using a combination of shotgun lipidomics and stable-isotope tracing, Hsieh et al. show that distinct pro-inflammatory stimuli reshape the macrophage lipid composition in a signal-specific manner and that targeting this change can increase immunity. Thus, the study provides an in-depth resource and framework for understanding this lipidomic response while suggesting approaches for future therapy. 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.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.
Author	Son, Young Min Flavell, Richard A. Chi, Xun Smale, Stephen T. Sun, Jie Williams, Kevin J. Khialeeva, Elvira York, Autumn G. Kaplan, Amber Kronenberger, Eliza B. Hoi, Xen Ping Bensinger, Steven J. Bui, Viet L. Zhou, Quan D. Su, Baolong Hsieh, Wei-Yuan Scumpia, Philip O. Divakaruni, Ajit S.
AuthorAffiliation	3 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA 6 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA 2 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA 11 Lead Contact 1 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA 5 Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA 9 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA 4 Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA 10 These authors contributed equally 8 Department of Immunology, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA 7 Howard Hughes Medical Institute
AuthorAffiliation_xml	– name: 9 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA – name: 7 Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA – name: 8 Department of Immunology, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA – name: 10 These authors contributed equally – name: 3 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA – name: 2 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA – name: 1 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA – name: 4 Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA – name: 5 Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA – name: 6 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA – name: 11 Lead Contact
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Keywords	macrophages toll-like receptors stable isotope tracer analysis inflammation stearoyl-CoA desaturase host defense acetylated-LDL interferon MyD88 lipidomics
Language	English
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS W.Y.H., Q.Z., and A.G.Y. conceptualized, designed/implemented experiments, analyzed data, and constructed the manuscript; K.J.W., P.O.S., V.L.B., E.K., X.P.H, X.C., A.Z., A.K., and A.S.D. designed, implemented experiments, and analyzed data; L.K., D.Q., B.L.S., and K.J.W. provided lipidomics and computational analysis; S.T.S. and R.A.F. provided resources and supervision, contributed to conceptualization, and revision of the manuscript; S.J.B. provided resources and supervision, and contributed to conceptualization, designed experiments, analyzed data, and construction of the manuscript.
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Snippet	Macrophages reprogram their lipid metabolism in response to activation signals. However, a systems-level understanding of how different pro-inflammatory...
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SubjectTerms	acetylated-LDL Animals Cell Line host defense inflammation interferon Lipidomics macrophages Macrophages - metabolism Male Mice Mice, Knockout Mice, Transgenic MyD88 Signal Transduction stable isotope tracer analysis stearoyl-CoA desaturase toll-like receptors Toll-Like Receptors - metabolism
Title	Toll-Like Receptors Induce Signal-Specific Reprogramming of the Macrophage Lipidome
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