炎症体
铁蛋白
肠沙门氏菌
微生物学
炎症
沙门氏菌
生物
细胞因子
免疫学
髓样
缺铁
败血症
促炎细胞因子
医学
细菌
生物化学
内科学
贫血
遗传学
作者
David Haschka,Piotr Tymoszuk,Verena Petzer,Richard Hilbe,Simon Heeke,Stefanie Dichtl,Sergej Skvortsov,Egon Demetz,Sylvia Berger,Markus Seifert,Anna-Maria Mitterstiller,Patrizia Moser,Dirk Bumann,Manfred Nairz,Igor Theurl,Günter Weiss
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2021-07-08
卷期号:6 (13)
被引量:4
标识
DOI:10.1172/jci.insight.141760
摘要
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+/+Fthfl/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+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β 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-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis.
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