Editors' ChoiceImmunology

Ironing Out Macrophages

Science Signaling  29 Apr 2014:
Vol. 7, Issue 323, pp. ec112
DOI: 10.1126/scisignal.2005415

Reduction of serum iron (hypoferremia) is a common host defense mechanism for limiting the growth of extracellular bacteria during infection (see Lokken et al.). The peptide hormone hepcidin is produced in the liver and promotes hypoferremia by simulating degradation of the iron channel ferroportin, thus reducing both the uptake of dietary iron and the release of iron into the bloodstream by the macrophages that recycle red blood cells. As the serum concentration of iron decreases, iron accumulates in hepatic and splenic macrophages. Kim et al. report that the intracellular pathogen Salmonella enterica var. Typhimurium (S. typhimurium) exploits this system to proliferate in macrophages. S. typhimurium infection causes the host to produce the proinflammatory cytokine interleukin-6 (IL-6), which activates Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling downstream of the IL-6 receptor. Experiments using various knockout mice, in vivo overexpression methods, and rat primary hepatocytes demonstrated that IL-6 induced by infection with S. typhimurium activated the transcription factor STAT3 in hepatocytes. Activated STAT3 directly stimulated the expression of the gene encoding the estrogen-related receptor γ (ERRγ), which, in turn, directly stimulated transcription of the gene encoding hepcidin. Injecting mice with the ERRγ inverse agonist GSK5182 before and during infection with an antibiotic-resistant strain of S. typhimurium resulted in reduced iron concentrations and bacterial numbers in the liver, decreased serum hypoferremia, and increased survival. This study not only adds iron homeostasis to the list of metabolic processes influenced by ERRγ but also suggests that preventing or reversing the iron accumulation that occurs in macrophages because of IL-6–induced hypoferremia might be a way to treat infection by S. typhimurium and other intracellular pathogens.

D.-K. Kim, J.-H. Jeong, J.-M. Lee, K. S. Kim, S.-H. Park, Y. D. Kim, M. Koh, M. Shin, Y. S. Jung, H.-S. Kim, T.-H. Lee, B.-C. Oh, J. I. Kim, H. T. Park, W.-I. Jeong, C.-H. Lee, S. B. Park, J.-J. Min, S.-I. Jung, S.-Y. Choi, H. E. Choy, H.-S. Choi, Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat. Med. 20, 419–424 (2014).[PubMed]

K. L. Lokken, R. M. Tsolis, A. J Bäumler, Hypoferremia of infection: A double-edged sword? Nat. Med. 20, 335–337 (2014). [PubMed]