Upon activation by a virus or bacteria or their products, macrophages and other immune cells undergo dramatic metabolic changes (reviewed in Refs. [1,2]). For example, lipopolysaccharide (LPS) causes a switch from oxidative phosphorylation to glycolysis in macrophages, leading to increased lactate production and rapid ATP production to fuel the inflammatory response [3]. Changes also occur in several other metabolic pathways such as the tricarboxylic acid (TCA) cycle and amino acid and lipid metabolism, leading to the accumulation of certain metabolites [4]. A novel role for several of these metabolic components, outside regular metabolism, in the immune response, has been elucidated over the past decade or so 2, 3. These metabolic changes help the cells, both directly and indirectly, to fight invading pathogens.

The metabolite itaconate (ITA) has emerged as a key immunoregulator in macrophages and is an important component of the host defense against pathogens. ITA is an α,β-unsaturated dicarboxylic acid (C5H6O4). It was first discovered in 1836 by Swiss chemist Samuel Baup, as an industrial product of citric acid distillation [5]. In the early 1970s, it was shown that ITA could inhibit the bacterial enzyme, isocitrate lyase (ICL), from several different bacteria 6, 7, 8. The role of ITA in innate immunity was expanded in 1995 when Lee et al. [9] discovered that Irg1 was highly upregulated in macrophages stimulated by LPS, and then in 2013, it was confirmed that ACOD1 (encoded by the gene Irg1) was the enzyme that catalyzed the production of ITA via the decarboxylation of cis-aconitate [10]. ACOD1 was then shown to be upregulated, in many cell types, by various immune stimuli 2, 11•, 12, 13. In this review, we will focus on the most recent discoveries regarding ITA, whose biology continues to surprise. ITA has been shown to have antibacterial and antiviral effects, as well as, in certain contexts, limiting inflammation (Figure 1). We will also examine the ways in which pathogens can evade the mechanisms of action of ITA and manipulate ITA for their own gain.