Iron Metabolism in Immune Response Dynamics

Iron is a vital micronutrient that underpins key processes in both innate and adaptive immunity. Its redox properties enable electron transfer in enzymes that generate reactive oxygen species for microbial killing, fuel mitochondrial energy production in proliferating lymphocytes and catalyse epigenetic modifications that regulate gene expression. Systemically, iron levels are tightly controlled by the liver‐derived peptide hepcidin, which modulates iron export from macrophages and enterocytes to maintain circulating iron within a narrow range. During infection and inflammation, hepcidin induction leads to hypoferremia, a defence mechanism that restricts pathogen access to extracellular iron but may also limit iron availability to host cells. Within tissues, specialised macrophage subsets recycle iron from senescent erythrocytes and redistribute it to support erythropoiesis and immune cell function. Dysregulation of these pathways contributes to anaemia of inflammation, impaired lymphocyte proliferation and chronic inflammatory states. A growing body of research highlights how precise iron allocation governs the balance between host defence and immunopathology, with implications for infection susceptibility, vaccine responsiveness and therapeutic manipulation of iron pathways in immune‐mediated diseases.

Research from Nature Portfolio

Recent studies have revealed that persistent disturbances in iron homeostasis are linked to prolonged inflammatory sequelae following viral infection. Analyses of individuals recovering from severe respiratory virus infection demonstrated unresolving inflammation, chronic low serum iron and a signature of stress erythropoiesis that predicted long‐term symptom persistence. Single‐cell profiling indicated abnormal iron distribution at the cellular level, with monocytes exhibiting iron loading and proliferating lymphocytes facing increased iron demand, suggesting that targeted modulation of iron handling may alleviate post‐infectious syndromes.

Complementary work has elucidated an epigenetic mechanism by which iron directly influences humoral immunity. It was shown that iron‐dependent histone demethylases catalyse removal of repressive marks on the cyclin E1 promoter in activated B cells, thereby promoting cell cycle progression and antibody production. Iron deficiency or pharmacological inhibition of these demethylases impaired B cell proliferation and attenuated vaccine‐induced antibody responses, underscoring the essential role of iron in epigenetic control of adaptive immunity.

Iron Metabolism in Immune Response Dynamics publication trend

The graph below shows the total number of articles in iron metabolism in immune response dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Hepcidin: A liver‐derived peptide that regulates systemic iron levels by inducing degradation of the iron exporter ferroportin.

Ferroportin: The sole known cellular iron exporter that controls release of iron from enterocytes, macrophages and hepatocytes.

Nutritional immunity: Host defence strategy involving withdrawal of essential nutrients, notably iron, to limit pathogen growth.

Stress erythropoiesis: Enhanced production of red blood cells under inflammatory conditions, often associated with altered iron distribution.

Histone demethylase: An enzyme that removes methyl groups from histone proteins, influencing gene expression in an iron‐dependent manner.

References

1. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nature Immunology (2024).
2. Metabolic immunity against microbes. Trends in Cell Biology (2023).
3. Why cells need iron: a compendium of iron utilisation. Trends in Endocrinology and Metabolism (2024).
4. Hepcidin and Host Defense against Infectious Diseases. PLOS Pathogens (2015).
5. “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflügers Archiv - European Journal of Physiology (2017).
6. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses. Nature Communications (2019).
7. Iron Metabolism and Immune Regulation. Frontiers in Immunology (2022).
8. Role of Hepcidin in the Setting of Hypoferremia during Acute Inflammation. PLOS ONE (2013).