Immune Response Gene 1 Links Metabolism to Immunity

Friday, May 10, 2013 - 2:00pm
Fung Auditorium | Powell-Focht Bioengineering Hall
Karsten Hiller, Ph.D.

Dr. rer. nat. in Bioinformatics and Microbiology

Luxembourg Centre for Systems Biomedicine

Immune Response Gene 1 Links Metabolism to Immunity

We revealed a yet unknown metabolic pathway for the production of an antimicrobial compound. Having profiled the metabolome of microglial cells and macrophages with and without LPS treatment, we identified an intracellular and highly abundant metabolite synthesized only under inflammatory conditions: itaconic acid. Applying stable-isotope labeling experiments, it could be demonstrated that this metabolite is produced in the TCA cycle from cis-aconitate. However, the mammalian metabolic pathway for the production of itaconic acid as well as its function in mammals have not been described. Here, we demonstrate that the immune response gene 1 (IRG1) is the mammalian gene coding for an enzyme catalyzing the decarboxylation of cis-aconitate to produce itaconic acid. We purified the mammalian IRG1 protein and could show itaconic acid production in an enzymatic assay. It is known that this metabolite inhibits the glyoxylate shunt needed by many bacteria to survive during infection. We confirmed the growth inhibitory effect of itaconic acid by supplementing different concentrations of the compound to the growth medium of Mycobacterium tuberculosis and Salmonella typhimurium. To test for the intracellular antimicrobial function of itaconic acid, we silenced the IRG1 gene in RAW263.7 mouse macrophages to decrease the intracellular level of the metabolite under inflammatory conditions. We could show a decreased killing activity of these impaired macrophages when infected with S. typhimurium.

Karsten Hiller is the head of the metabolomics group at the Luxembourg Centre for Systems Biomedicine. He obtained his diploma in biology and computer science. He performed his PhD in bioinformatics and microbiology at the University of Braunschweig, Germany and focused on the development of algorithms for the analysis of metabolomics data. He had an appointment as a postdoc in the group of Gregory Stephanopoulos at the department of Chemical Engineering, MIT where he worked on stable-isotope assisted metabolomics and cancer metabolism. His current work focuses on cellular metabolism in the context of inflammation and neurodegeneration. The current research is mainly funded by the ATTRACT research program of the Fonds Nationale de la Recherche Luxembourg (FNR).