Itaconic acid mainly exerts anti-inflammatory function in macrophages. As a metabolite produced by the tricarboxylic acid cycle, itaconic acid can inhibit the activity of succinate dehydrogenase in the mitochondria, thereby reducing the generation of mitochondrial reactive oxygen species, and finally achieve the effect of weakening the inflammatory response. In addition, itaconic acid can also shuttle from the mitochondrial matrix into the cytoplasm. In the cytoplasm, the main mechanism for itaconate to exert its anti-inflammatory function is to modify the cysteine residues of related proteins through the alkylation of thia-Michael addition reaction. For example, modify KEAP1 (Kelch like ECH associated protein 1) protein by alkylation and activate Nrf2 signaling pathway to reduce the inflammatory response and oxidative stress of macrophages.
Itaconic acid also has antibacterial effects. Since 1977, scientists have discovered that itaconic acid inhibits the growth of Pseudomonas indigo under glucose-deprived conditions. Itaconic acid mainly inhibits the activity of isocitrate lyase in bacteria, thereby blocking the glyoxylate shunt pathway required for bacterial growth and pathogenicity, and then exerts its antibacterial effect. In addition, itaconyl-CoA, an intermediate metabolite of itaconic acid, can inhibit the activity of methylmalonyl-CoA mutase in bacteria, thereby blocking the growth of propionyl-CoA-dependent bacteria, such as Mycobacterium tuberculosis. The author’s postdoctoral research found that under the condition of macrophages infected by bacteria, itaconic acid-mediated TFEB alkylation induces the biosynthesis of lysosomes in macrophages, thereby enhancing the body’s antibacterial innate immunity. Our research expands other important biological functions of itaconic acid besides anti-inflammatory.
Itaconic acid enhances the body’s antibacterial ability by inducing lysosomal biosynthesis
Figure 2. Itaconic acid enhances the antibacterial ability of the body by inducing lysosomal biosynthesis
When macrophages find bacterial invasion, they will respond immediately to release itaconic acid from mitochondria. Itaconic acid modifies TFEB through alkylation to activate its nuclear entry and promote the biosynthesis of lysosomes, thereby destroying the invading bacteria.
Interestingly, itaconic acid also exhibited antiviral effects. For example, itaconic acid derivatives inhibit the replication of Zika virus, herpes simplex virus and vaccinia virus. This suggests that itaconic acid has the potential to treat viral infections.
