High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3

Dominic De Nardo; Larisa I Labzin; Hajime Kono; Reiko Seki; Susanne V Schmidt; Marc Beyer; Dakang Xu; Sebastian Zimmer; Catharina Lahrmann; Frank A Schildberg; Johanna Vogelhuber; Michael Kraut; Thomas Ulas; Anja Kerksiek; Wolfgang Krebs; Niklas Bode; Alena Grebe; Michael L Fitzgerald; Nicholas J Hernandez; Bryan R G Williams; Percy Knolle; Manfred Kneilling; Martin Röcken; Dieter Lütjohann; Samuel D Wright; Joachim L Schultze; Eicke Latz

doi:10.1038/ni.2784

High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3

Nat Immunol. 2014 Feb;15(2):152-60. doi: 10.1038/ni.2784. Epub 2013 Dec 8.

Authors

Dominic De Nardo¹, Larisa I Labzin¹, Hajime Kono², Reiko Seki³, Susanne V Schmidt⁴, Marc Beyer⁴, Dakang Xu⁵, Sebastian Zimmer⁶, Catharina Lahrmann⁶, Frank A Schildberg⁷, Johanna Vogelhuber⁸, Michael Kraut⁴, Thomas Ulas⁴, Anja Kerksiek⁹, Wolfgang Krebs⁴, Niklas Bode⁶, Alena Grebe⁸, Michael L Fitzgerald¹⁰, Nicholas J Hernandez¹⁰, Bryan R G Williams¹¹, Percy Knolle¹², Manfred Kneilling¹³, Martin Röcken¹⁴, Dieter Lütjohann⁹, Samuel D Wright¹⁵, Joachim L Schultze¹⁶, Eicke Latz¹⁷

Affiliations

¹ 1] Institute of Innate Immunity, University Hospitals, Biomedical Centre, University of Bonn, Bonn, Germany. [2].
² Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
³ Department of Clinical Laboratory Science, Teikyo University Faculty of Medical Technology, Tokyo, Japan.
⁴ Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
⁵ 1] Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia. [2] Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China.
⁶ Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
⁷ Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
⁸ Institute of Innate Immunity, University Hospitals, Biomedical Centre, University of Bonn, Bonn, Germany.
⁹ Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
¹⁰ Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia.
¹² 1] Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany. [2] Institute of Molecular Immunology, Technical University of Munich, Munich, Germany.
¹³ 1] Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. [2] Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tuebingen, Germany.
¹⁴ Department of Dermatology, Eberhard Karls University, Tuebingen, Germany.
¹⁵ Cardiovascular Therapeutics, CSL Limited, Parkville, Australia.
¹⁶ 1] Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. [2].
¹⁷ 1] Institute of Innate Immunity, University Hospitals, Biomedical Centre, University of Bonn, Bonn, Germany. [2] Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [3] German Center for Neurodegenerative Diseases, Bonn, Germany. [4].

PMID: 24317040
PMCID: PMC4009731
DOI: 10.1038/ni.2784

Abstract

High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional regulator ATF3, as an HDL-inducible target gene in macrophages that downregulates the expression of Toll-like receptor (TLR)-induced proinflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of new HDL-based therapies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 3 / genetics
Activating Transcription Factor 3 / metabolism*
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
Atherosclerosis / therapy*
Cells, Cultured
Cholesterol / metabolism*
Chromatin Immunoprecipitation
Cytokines / metabolism
Female
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Inflammation / therapy*
Lipoproteins, HDL / pharmacology
Lipoproteins, HDL / therapeutic use*
Macrophage Activation / drug effects
Macrophages / drug effects*
Macrophages / immunology
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Systems Biology
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / immunology

Substances

Activating Transcription Factor 3
Anti-Inflammatory Agents, Non-Steroidal
Atf3 protein, mouse
Cytokines
Lipoproteins, HDL
Toll-Like Receptor 4
Cholesterol

Associated data

GEO/GSE44034

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding