Iron sequestration is a biological process where the body isolates and stores iron. This mechanism addresses the “iron paradox”: while iron is essential for many biological functions, its free form can be damaging to cells. Unbound iron can catalyze reactions that produce harmful molecules, leading to oxidative stress and cellular damage. Sequestering iron is a tightly regulated function that safeguards health.
The Body’s Iron Management System
The body manages iron to ensure its availability for essential processes while preventing toxic accumulation. Ferritin is the main intracellular iron storage protein. It functions like a secure cellular vault, holding up to 4500 iron atoms in a non-toxic form, releasing them when cells require iron.
Transferrin, another key protein, transports iron through the bloodstream. It safely moves iron from absorption centers in the gut and from iron-recycling cells to various tissues, including bone marrow for red blood cell production. Nearly all iron circulating in the plasma is bound to transferrin, preventing harm. The liver serves as a central command center for this system, producing proteins like hepcidin and acting as a major storage site for excess iron.
Iron Sequestration as an Immune Defense
Beyond its role in daily iron balance, iron sequestration is a primary strategy of the innate immune system, often called “nutritional immunity.” This defense limits essential micronutrients, like iron, to invading pathogens. During infection or inflammation, the body deliberately reduces free iron in the bloodstream.
Hepcidin, a hormone produced by the liver, orchestrates this process. In response to inflammatory signals, hepcidin levels increase. Elevated hepcidin binds to ferroportin, the protein responsible for exporting iron from cells. This binding causes ferroportin to be degraded, trapping iron within storage cells like macrophages and gut lining cells. By preventing iron release into circulation or absorption, the body “starves” iron-dependent pathogens, hindering their growth and proliferation.
Consequences of Dysregulated Iron Sequestration
While iron sequestration is a protective immune response, its dysregulation can lead to unintended health consequences. Anemia of Chronic Disease (ACD), also known as Anemia of Inflammation, is a notable example. This condition develops in individuals with long-term inflammatory states, such as autoimmune diseases, chronic infections, or cancer.
Persistently high levels of hepcidin, driven by ongoing inflammation, cause excessive iron sequestration. Hepcidin traps iron within macrophages and reduces intestinal iron absorption, making it unavailable for red blood cell production. This leads to a functional iron deficiency, where the body has sufficient iron stores, but the iron is locked away and cannot be utilized for red blood cell production.
Unlike iron deficiency anemia, where total body iron stores are low, ACD is characterized by low circulating iron despite normal or even elevated iron stores. This imbalance underscores the delicate nature of iron regulation and the potential for a protective immune strategy to contribute to systemic health issues when prolonged. In contrast, conditions like hemochromatosis involve a failure to properly sequester iron, leading to excessive absorption and toxic iron overload in organs like the liver, heart, and pancreas, causing damage.