Format

Send to

Choose Destination
Cell Metab. 2019 Jan 8;29(1):211-220.e5. doi: 10.1016/j.cmet.2018.09.003. Epub 2018 Oct 4.

The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity.

Author information

1
Department of Internal Medicine (463) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands. Electronic address: jorge.dominguezandres@radboudumc.nl.
2
Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen 6525 GA, the Netherlands.
3
Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
4
Center of Experimental & Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
5
Department of Internal Medicine (463) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
6
Department of Internal Medicine (463) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands.
7
Department of Intensive Care and Radboud Center for Infectious diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands.
8
NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Belval, Luxembourg.
9
Department of Internal Medicine (463) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands; Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.
10
Department of Internal Medicine (463) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert Grooteplein 8, Nijmegen 6500 HB, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany; Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania.

Abstract

Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by β-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. β-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH polymorphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune tolerance and training and highlight the potential of β-glucan-induced trained immunity to revert immunoparalysis.

KEYWORDS:

LPS; epigenetics; immunoparalysis; itaconate; metabolism; monocytes; sepsis; succinate; tolerance; trained immunity

PMID:
30293776
DOI:
10.1016/j.cmet.2018.09.003

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center