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

26 October 2018

Recently, Jorge Domínguez-Andrés and Mihai Netea, theme Infectious diseases and global health, and colleagues, demonstrate in Cell Metabolism, the importance of the IRG1-itaconate-SDH axis in the development of immune tolerance and trained immunity, and highlight the potential of β-glucan as a tool to revert immune paralysis induced by sepsis.

Publication in Cell Metabolism.
Jorge Dominquez-Andrés (photo left)
Mihai Netea (photo right)

The disruption of the bioenergetic pathways of the cells of the immune system leads to a failure to establish a proper response to infectious diseases. Itaconate is an endogenous metabolite that has been widely employed in different industrial processes for decades. However, a growing number of studies have recently shown that this metabolite is able to induce profound metabolic changes in immune cells occur after exposure to pathogens, when it is synthesized as an antimicrobial compound from Krebs cycle intermediates.

In this report, the authors describe that the production of itaconate plays a central role in inducing immunosuppression in human monocytes in the context of sepsis. In addition, they describe that β-glucan, a fungal cell wall component that exerts a long-term upregulation of innate immune function effects on monocytes and macrophages termed ‘‘trained immunity’’, counteracts this effect by maintaining the integrity of different metabolic pathways of the immune cells. By preserving the functionality of these pathways, the treatment with β-glucan was able to reverse the immune paralysis state induced by endotoxins. These data identify itaconate metabolism as a crucial regulatory node between tolerance and trained immunity and makes it an attractive therapeutic target in sepsis, a clinical condition that affects an estimated number of 20 and 30 million people worldwide every year, representing a leading cause of death in both developed and developing countries.

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