Plasma iron controls neutrophil production and function

Abstract

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.

Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm

“…44 Of note, recent evidence has shown that neutrophils have a particularly high cellular demand for iron. 45 The finding that AngII altered systemic iron indices (Figure S5) raises the wider question of whether there is an interplay between Angiotensin-II signalling and systemic iron homeostasis. This notion is supported by findings from others, [46][47][48] and further studies are warranted to explore this potential interplay and identify its mechanisms.…”

“… 44 Of note, recent evidence has shown that neutrophils have a particularly high cellular demand for iron. 45 …”

Iron controls the development of airway hyperreactivity by regulating ILC2 metabolism and effector function

“…Recent studies begin to reveal the importance of iron in immune cell function and disease development, with evidence that iron deficiency limits adaptive immunity ( 12 ). An elegant mathematical approach recently predicted the iron needs of resting leukocytes ( 13 ). Although all cell populations analyzed were predicted to have at least 30 × 10 6 atoms of iron per cell at steady state, a recent report described the critical requirement of iron during T cell activation ( 14 ).…”

Cellular iron governs the host response to malaria

“…Immune cells with high proliferative and anabolic capacities appear to be particularly sensitive to iron deficiency. As such, decreased iron availability can impair the proliferation and maturation of lymphocytes and neutrophils (14–16).…”

“…Neutrophils and macrophages also require iron for enzymes involved in microbial killing (16–20). In animal models of iron deficiency, lymphocyte function is severely impaired, and the immune response to immunisation and viral infection is inhibited (21, 22).…”