Plasma iron controls neutrophil production and function.
Joe N FrostSarah Karin WidemanAlexandra E PrestonMegan R TehZhichao AiLihui WangAmy CrossNatasha WhiteYavuz YaziciogluMichael BonadonnaAnna Katharina SimonAndrew E ArmitageBruno GalyIrina A UdalovaAlexander DrakesmithPublished in: Science advances (2022)
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 neutropenia 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.
Keyphrases
- dendritic cells
- iron deficiency
- oxidative stress
- inflammatory response
- peripheral blood
- diabetic rats
- drug induced
- reactive oxygen species
- high glucose
- type diabetes
- transcription factor
- signaling pathway
- bone marrow
- electronic health record
- mesenchymal stem cells
- big data
- intensive care unit
- deep learning
- lps induced
- artificial intelligence
- acute respiratory distress syndrome
- wound healing
- aortic dissection