The IRG1-Itaconate axis: A regulatory hub for immunity and metabolism in macrophages

Abstract

Metabolism could be served as a guiding force for immunity, and macrophages undergo drastic metabolic reprogramming during inflammatory processes, including enhancing glycolysis and reshaping the tricarboxylic acid cycle (TCA) cycle. The disrupted TCA cycle facilitates itaconate accumulation, consistent with the significant up-regulation of immune response gene 1 (IRG1) in activated macrophages. IRG1 catalyzes the decarboxylation of cis-aconitate to synthesize itaconate, and notably, the IRG1-Itaconate axis has excellent potential to link macrophages’ immunity and metabolism. Here, we review vital molecules that affect the activation of the IRG1-Itaconate axis, including interferon regulatory factor 1/9 (IRF1/9), transcription 1 and 3 (STAT1/3), CCAAT enhancer-binding protein β (C/EBPβ), and the protein kinase C (PKC). We then focus on how the IRG1-Itaconate axis regulates the inflammatory pathway in macrophages, proposed to involve kelch-like ECH-associated protein 1 (Keap1), NOD-, LRR- and pyrin domain-containing 3 (NLRP3), gasdermin D (GSDMD), activating transcription factor 3 (ATF3), receptor-interacting protein kinase-3 (RIPK3), et al. In addition, we provide an overview of the way the axis participates in the metabolism of macrophages. Eventually, we summarize current connections between the IRG1-Itaconate axis and inflammatory diseases, bringing light to new therapeutic opportunities in inflammatory diseases.

Graphical Abstract

Keywords:

• IRG1
• itaconate
• immunity
• metabolism
• macrophage

Authors’ contributions

All authors contributed to the design of the article. Yangguang Li wrote the manuscript which was revised by Xiuwen Wu, Yun Zhao, and Jianan Ren. All authors approved the final manuscript.

Availability of data and materials

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by 333 High Level Talents Training Project of Jiangsu Province (BRA2019011), National Natural Science Foundation of China (82072149), the Natural Science Foundation of Jiangsu Province (BK20201116, BK20210039), the Medical Scientific Research Project of Jiangsu Provincial Health Commission (ZDB2020028), Distinguished Medical Expert of Jiangsu Province.