Does iron deficiency impair immune cell function and promote dysregulated inflammation?

Iron is a fundamental nutrient for the immune system, serving as an essential cofactor for metabolic and enzymatic processes that govern both innate and adaptive immune responses. Deficiencies in iron status, regardless of whether anemia is present, lead to quantifiable impairments in immune cell proliferation and the regulation of systemic inflammation.

Mechanisms of immune impairment

Iron is vital for the metabolic health of immune cells, particularly through its role in DNA synthesis and energy production:

• Adaptive immunity: T-cell and B-cell proliferation depends on ribonucleotide reductase (RNR), an iron-dependent enzyme that catalyzes the rate-limiting step of DNA synthesis. Iron deficiency disrupts this process and impairs histone demethylases (like KDM2B), which are required for cell cycle progression (S-phase entry).
• Innate immunity: Iron is a central component of the mitochondrial electron transport chain. Low iron availability suppresses oxidative phosphorylation (OXPHOS), which prevents the proper activation and polarization of macrophages and natural killer (NK) cells.
• Clinical consequences: These cellular deficits often translate to a 3- to 4-fold increased risk of infection and diminished antibody production following vaccination.

Dysregulated inflammatory responses

Iron deficiency is strongly associated with a state of chronic, low-grade inflammation, often characterized by elevated biomarkers such as high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6):

• The Hepcidin Axis: Inflammation triggers the production of hepcidin, which sequesters iron within macrophages. Conversely, low systemic iron can sustain inflammatory signaling, creating a bidirectional cycle where iron restriction and systemic inflammation reinforce one another.
• Biomarker evidence: Research indicates that individuals with iron deficiency anemia exhibit significantly higher plasma levels of TNF-α and IL-6 compared to healthy controls. Interventions such as iron supplementation have been shown to reduce these inflammatory markers while restoring iron parameters.

Bottom line

Iron deficiency directly impairs immune cell function by stalling DNA synthesis and mitochondrial metabolism, while simultaneously promoting dysregulated systemic inflammation through the hepcidin-IL-6 axis. Addressing iron status is critical for maintaining robust immune defenses and regulating the inflammatory response.