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Abstract
Itaconic acid is produced by immune responsive gene 1 (IRG1)-coded enzyme in activated macrophages and known to play an important role in metabolism and immunity. In this study, mechanism of itaconic acid functioning as an anti-inflammatory metabolite was investigated with molecular biology and immunology techniques, by employing IRG1-null (prepared with CRISPR) and wild-type macrophages. Experimental results showed that itaconic acid significantly promoted the pentose phosphate pathway (PPP), which subsequently led to significantly higher NADPH oxidase activity and more reactive oxygen species (ROS) production. ROS production increased the expression of anti-inflammatory gene A20, which in turn decreased the production of inflammatory cytokines IL-6, IL-1β and TNF-α. NF-κB, which can up-regulate A20, was also vital in controlling IRG1 and itaconic acid involved immune-modulatory responses in LPS-stimulated macrophage in this study. In addition, itaconic acid inhibited the growth of Salmonella typhimurium in cell through increasing ROS production from NADPH oxidase and the hatching of Schistosoma japonicum eggs in vitro. In short, this study revealed an alternative mechanism by which itaconic acid acts as an anti-inflammatory metabolite and confirmed the inhibition of bacterial pathogens with itaconic acid via ROS in cell. These findings provide the basic knowledge for future biological applications of itaconic acid in anti-inflammation and related pathogens control.
Highlights
Itaconic acid is produced by immune responsive gene 1 (IRG1)-coded enzyme in activated macrophages and known to play an important role in metabolism and immunity
The Schistosoma japonicum worm and egg burden of mice co-infected with both S. japonicum and S. typhimurium were significantly reduced, and the elevated level of itaconic acid caused by S. typhimurium coinfection may play an important role[6]
In order to evaluate the function of itaconic acid, CRISPR-Cas[9] was employed to delete the IRG1 gene in RAW264.7 cell line
Summary
Itaconic acid is produced by immune responsive gene 1 (IRG1)-coded enzyme in activated macrophages and known to play an important role in metabolism and immunity. Mechanism of itaconic acid functioning as an anti-inflammatory metabolite was investigated with molecular biology and immunology techniques, by employing IRG1-null (prepared with CRISPR) and wild-type macrophages. Itaconic acid inhibited the growth of Salmonella typhimurium in cell through increasing ROS production from NADPH oxidase and the hatching of Schistosoma japonicum eggs in vitro. Itaconic acid is an important mammalian metabolite which mediates the crosstalk between infection, immunity and metabolism It is produced by immune responsive gene 1 (IRG1)-coded enzyme which catalyzes cis-aconitic acid in activated macrophages under conditions of infection or pro-inflammation[1,2,3,4]. Our research provided understanding into new mechanisms of the anti-inflammatory effects of itaconic acid/IRG1 and shed new light on the anti-inflammatory functions of itaconate
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