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

被引：258

作者：

Dominguez-Andres, Jorge ^{[1
,2
]}

Novakovic, Boris ^{[3
]}

Li, Yang ^{[4
]}

Scicluna, Brendon P. ^{[5
]}

Gresnigt, Mark S. ^{[1
,2
,11
]}

Arts, Rob J. W. ^{[1
,2
]}

Oosting, Marije ^{[1
,2
]}

Moorlag, Simone J. C. F. M. ^{[1
,2
]}

Groh, Laszlo A. ^{[1
,2
]}

Zwaag, Jelle ^{[2
,6
]}

Koch, Rebecca M. ^{[2
,6
]}

ter Horst, Rob ^{[1
,2
]}

Joosten, Leo A. B. ^{[1
,2
]}

Wijmenga, Cisca ^{[4
]}

Michelucci, Alessandro ^{[7
,8
]}

van der Poll, Tom ^{[5
]}

Kox, Matthijs ^{[2
,6
]}

Pickkers, Peter ^{[2
,6
]}

Kumar, Vinod ^{[1
,2
,4
]}

Stunnenberg, Henk ^{[3
]}

Netea, Mihai G. ^{[1
,2
,9
,10
]}

机构：

[1] Radboud Univ Nijmegen, Dept Internal Med 463, Med Ctr, Geert Grootepl 8, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Radboud Ctr Infect Dis RCI, Med Ctr, Geert Grootepl 8, NL-6500 HB Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 GA Nijmegen, Netherlands

[4] Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[5] Univ Amsterdam, Ctr Expt & Mol Med, Amsterdam Med Ctr, Div Infect Dis, Amsterdam, Netherlands

[6] Radboud Univ Nijmegen, Dept Intens Care, Med Ctr, Geert Grootepl 8, NL-6500 HB Nijmegen, Netherlands

[7] Luxembourg Inst Hlth, Dept Oncol, NORLUX Neurooncol Lab, Luxembourg, Luxembourg

[8] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Belval, Luxembourg

[9] Univ Bonn, Life & Med Sci Inst LIMES, Dept Genom & Immunoregulat, Bonn, Germany

[10] Craiova Univ Med & Pharm, Human Genom Lab, Craiova, Romania

[11] Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, Dept Microbial Pathogen Mech, Jena, Germany

来源：

CELL METABOLISM | 2019年 / 29卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

SUCCINATE-DEHYDROGENASE; BETA-GLUCAN; ENDOTOXIN TOLERANCE; EXPERIMENTAL-MODEL; METABOLISM; GENE-1; MACROPHAGE; EXPRESSION; ALIGNMENT; SEPSIS;

D O I：

10.1016/j.cmet.2018.09.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 beta-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. beta-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 poly-morphisms 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 beta-glucan-induced trained immunity to revert immunoparalysis.

引用

页码：211 / +

页数：15