@article{82b464e99c8a4f54aa1f7aa31bd875e9,
title = "The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity",
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",
author = "Jorge Dom{\'i}nguez-Andr{\'e}s and Boris Novakovic and Yang Li and Scicluna, {Brendon P.} and Gresnigt, {Mark S.} and Arts, {Rob J.W.} and Marije Oosting and Moorlag, {Simone J.C.F.M.} and Groh, {Laszlo A.} and Jelle Zwaag and Koch, {Rebecca M.} and {ter Horst}, Rob and Joosten, {Leo A.B.} and Cisca Wijmenga and Alessandro Michelucci and {van der Poll}, Tom and Matthijs Kox and Peter Pickkers and Vinod Kumar and Henk Stunnenberg and Netea, {Mihai G.}",
note = "Funding Information: We thank Richard C. Hartley for 4-octyl itaconate. This study was partly supported by TOP grants from the Netherlands Organization for Scientific Research (to M.G.N., H.S., and T.v.d.P.). M.G.N. was supported by an ERC Consolidator Grant (no. 310372 ) and by a Spinoza Grant from the Netherlands Organisation for Scientific Research . B.N. is supported by an NHMRC (Australia) CJ Martin Fellowship. Funding Information: We thank Richard C. Hartley for 4-octyl itaconate. This study was partly supported by TOP grants from the Netherlands Organization for Scientific Research (to M.G.N., H.S., and T.v.d.P.). M.G.N. was supported by an ERC Consolidator Grant (no. 310372) and by a Spinoza Grant from the Netherlands Organisation for Scientific Research. B.N. is supported by an NHMRC (Australia) CJ Martin Fellowship. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2019",
month = jan,
day = "8",
doi = "10.1016/j.cmet.2018.09.003",
language = "English",
volume = "29",
pages = "211--220.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}