Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages 
during inflammation, but its biological function has not yet been elucidated. 
Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid 
(also known as methylenesuccinic acid) through the decarboxylation of 
cis-aconitate, a tricarboxylic acid cycle intermediate. Using a 
gain-and-loss-of-function approach in both mouse and human immune cells, we 
found Irg1 expression levels correlating with the amounts of itaconic acid, a 
metabolite previously proposed to have an antimicrobial effect. We purified IRG1 
protein and identified its cis-aconitate decarboxylating activity in an 
enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate 
lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial 
growth under specific conditions. Here we show that itaconic acid inhibits the 
growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and 
Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages 
resulted in significantly decreased intracellular itaconic acid levels as well 
as significantly reduced antimicrobial activity during bacterial infections. 
Taken together, our results demonstrate that IRG1 links cellular metabolism with 
immune defense by catalyzing itaconic acid production.