期刊
SCIENCE ADVANCES
卷 8, 期 40, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abq5384
关键词
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资金
- U.K. Medical Research Council (MRC Human Immunology Unit) [MCU_12010/10]
- Wellcome Trust Infection, Immunology and Translational Medicine doctoral program [108869/Z/15/Z]
- Clarendon Fund
- Corpus Christi College A. E. Haigh graduate scholarship
- Oxford-BMS Fellowship
- Deutsche Forschungsgemeinschaft [GA2075/5-1, GA2075/6.1]
- Wellcome Trust [209422/Z/17/Z, 211072/Z/18/Z]
- Novo Nordisk Foundation (Tripartite Immunometabolism Consortium)
- Chinese Science Council
- MeRIAD Consortium
- Wellcome Trust [211072/Z/18/Z, 209422/Z/17/Z] Funding Source: Wellcome Trust
Low plasma iron induced by hepcidin inhibits neutrophil production and alters their effector functions, while having no significant effect on other types of white blood cells. Antagonizing endogenous hepcidin can enhance neutrophil production during acute inflammation. These findings suggest that plasma iron plays a role in modulating the profile of innate immunity, with potential therapeutic implications.
Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes, or dendritic cells. Neutrophil rebound after anti-Gr-1-induced neutro-penia was blunted during hypoferremia but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically stimulated granulopoiesis mediated by granulocyte colony-stimulating factor and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial reactive oxygen species-dependent NETosis associated with chronic inflammation. Notably, antagonizing endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.
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