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Cell. 2018 Jan 11;172(1-2):162-175.e14. doi: 10.1016/j.cell.2017.12.013.

Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming.

Author information

1
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA.
2
Department for Genomics & Immunoregulation, and Myeloid Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany.
3
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
4
Center of Integrated Protein Science Munich (CIPSM) and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80337 Munich, Germany.
5
Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA.
6
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
7
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
8
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
9
Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, 77845 College Station, TX, USA.
10
Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
11
Lipid Metabolism Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
12
Department for Genomics & Immunoregulation, and Myeloid Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
13
Department for Genomics & Immunoregulation, and Myeloid Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
14
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany. Electronic address: eicke.latz@uni-bonn.de.

Abstract

Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed "trained immunity," causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr-/- mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3-/-/Ldlr-/- mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.

KEYWORDS:

ASC; NLRP3 inflammasome; Western diet feeding; atherosclerosis; epigenetic reprogramming; granulocyte macrophage progenitors; innate immune memory; non-communicable diseases; sterile inflammation; trained immunity

PMID:
29328911
PMCID:
PMC6324559
DOI:
10.1016/j.cell.2017.12.013
[Indexed for MEDLINE]
Free PMC Article

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