期刊
JCI INSIGHT
卷 6, 期 13, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.141760
关键词
-
资金
- Austrian Research Fund (FWF) [P 28302, P 33062, I 3321, W 1253]
- Austrian Academy of Sciences
- Osterreichische Krebshilfe Tirol [15024]
- Christian Doppler research Society
- Society for Funding Research and Education in Molecular Immunology and Infectiology (Verein zur Forderung von Forschung und Weiterbildung in Molekularer Immunologie und Infektiologie)
Iron is essential for both mammals and pathogens, and inflammation-induced changes in iron metabolism play a crucial role in host defense against infections. The iron storage protein FTH in myeloid cells is important for controlling bacterial spread and modulating NF-κB and inflammasome-mediated cytokine activation.
Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre(+/+)Fth(fl/fl) mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre(+/+)Fth(+/+) and LysM-Cre(+/+)Fth(fl/fl) animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre(+/+)Fth(fl/fl) mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-kappa B and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1 beta pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-kappa B and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据