The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity.

January 08, 2019 By:
  • Dominguez-Andres J
  • Novakovic B
  • Li Y
  • Scicluna BP
  • Gresnigt MS
  • Arts RJW
  • Oosting M
  • Moorlag S
  • Groh LA
  • Zwaag J
  • Koch RM
  • Ter Horst R
  • Joosten LAB
  • Wijmenga C
  • Michelucci A
  • van der Poll T
  • Kox M
  • Pickkers P
  • Kumar V
  • Stunnenberg H
  • Netea MG.

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 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 beta-glucan-induced trained immunity to revert immunoparalysis.

2019 Jan. Cell Metab.29(1):211-220 e5. Epub 2018 Oct 4.
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