Inflammation and Micronutrient Flux

The acute inflammatory reaction is a coordinated and complex series of physiological and immune adaptations designed to optimize protection to an invading pathogen. Immune cells are activated and cytokines released (e.g., IL-1 and TNF) to increase endothelial permeability and chemotaxis and activate complement. Effector immune cells are thus brought to a site of tissue injury and activated. Cytokines mediate the dramatic changes in the micronutrient milieu that accompanies inflammation. Plasma levels of both iron and zinc fall as both micronutrients are withdrawn from readily available pools and diverted to the reticulo-endothelial system so as to both optimize immune response and deny access to invading pathogens. Decreased iron absorption, decreased iron release from reticuloendothelial macrophages, and increased transferrin catabolism contribute to iron withdrawal. Macrophagal sequestration of iron is mediated by inflammatory cytokines. Cellular iron homeosta-sis is a post-transcriptional event and expression of the transferrin receptor limits acquisition of iron. Iron-response proteins (IRP) 1 and 2 bind to iron-responsive elements (IRE) in transferrin receptor and ferritin mRNA and thus regulate expression of these genes and uptake, utilization, and storage of intracellular iron. Inflammatory cytokines modulate intracellular iron status by regulating the IRP/ IRE network. Proinflammatory cytokines released during inflammation, e.g., TNF-a and IL-1, increases ferritin transcription and induce a diversion of metabolically available iron into the storage compartment in macrophages thus limiting iron availability for erythropoiesis. This diversion of iron underlies the anemia of inflammation/chronic disease.

Zinc is also diverted to the reticuloendothelial system during inflammation and lower plasma zinc concentrations are associated with both optimal phagocytic function and decreased microbial virulence. Calprotectin is an acute phase zinc-binding protein produced by polymorphonuclear leucocytes that sequesters zinc from invading pathogens. IL-1 released in inflammation increases the expression of metallothionen 1 and 2 in the liver, bone marrow, and thymus, which accompanies the increased uptake of zinc in these organs.

Iron and zinc are essential for microbial survival as cofactors for both superoxide dismutase and cat-alase redox enzyme systems. These enzymes neutralize the reactive oxygen intermediates integral to phagosomal killing. Both iron and zinc are also cofactors for bacterial enzymes required for DNA

Table 1 Immune effects of iron and zinc deficiency.



Effect of deficiency

Impaired lymphocyte proliferation Impaired delayed type hypersensitivity Impaired phagocytic function

Effect of overload

Impaired lymphocyte proliferation Impaired phagocytic function Impaired natural killer cell function

Effect of deficiency


Impaired T & B lymphocyte function Impaired phagocytic function Impaired gastrointestinal barrier function Impaired natural killer cell function Impaired complement function Impaired TH1/TH2 balance

Effect of overload

Impaired lymphocyte stimulation Impaired phagocytic function synthesis. Intracellular pathogens, e.g., tuberculosis, must acquire iron and polymorphic variants of host NRAMP1 (natural resistance-associated macrophage protein), which influence intramacrophagal flux of iron, can determine susceptibility to intracellular pathogens. The host macrophage uses iron to generate free radicals to kill Mycobacterium tuberculosis - the competition for essential micro-nutrients between the host and the invading microbe continues within immune cells. The control of iron flux during malaria may be important in determining the severity of malaria, the severity of postmalarial anemia, and the propensity to bacterial coinfection and may underlie the protective effect of hemoglobin, haptoglobin, and red cell enzyme variants. Oxidant stress accompanying the hemo-lysis of malaria is driven by free hemoglobin and is detrimental to both invading parasite and red blood cell membrane. The intraerythrocytic parasite degrades hemoglobin within its food vacuole and controls the resultant generation of free radicals by polymerizing free hemoglobin to hemozoin. Antimalarials, e.g., chloroquine, prevent this process and the parasite succumbs to its own waste. Hemoglobin, haptoglobin, or red cell enzyme variants that offer a more pro-oxidant environment can offer protection from severe malaria by ensuring earlier immune destruction of parasitized red cells. Strategies to manipulate hemolysis, oxidant stress, and iron flux during malarial episodes are key to the intraerythrocytic battle between host and parasite.

Correction of micronutrient deficiencies associated with defined functional consequences is a worthy goal. Iron and zinc deficiency are commonplace, particularly in children in developing countries, and have a significant effect on public health. Supplementation trials of zinc have been associated with significantly reduced infectious disease morbidity and mortality and there is good rationale for using targeted zinc supplementation to reduce infectious disease morbidity. Iron supplementation would not be advocated solely on the basis of its effect on infectious disease morbidity but this effect should be considered in supplementation programs. A recent meta-analysis showed

Figure 1 Micronutrient flux and the immune response to infection. (Adapted from Doherty CD, Weaver LT, and Prentice AM (2002) Micronutrient supplementation and infection: a double edged sword? Journal of Pediatric Gastroenterology and Nutrition 34: 346-352.)

no harmful effect of iron supplementation on overall infectious disease incidence. However, if micro-nutrient withdrawal is a deliberate immune defense strategy and the control of micronutrient flux is worthy of such genomic investment then interference with blanket micronutrient supplementation will likely have adverse effects for subgroups within those populations. Understanding host variability in response to supplementation, the effect of supplementation during infection and nutrient-gene interactions in both host and potential pathogen is key to identifying these subgroups and improving micronutrient targeting.

The objective of supplementation, dose, route, pre-existing level of deficiency, immunocompetence, coexistent deficiencies, genetic determinants, and the presence of infection should all be considered in the decision of who to supplement and when.

See also: Anemia: Iron-Deficiency Anemia. Bioavailability. Cytokines. Food Fortification:

Developed Countries; Developing Countries. Infection: Nutritional Interactions. Iron. Supplementation: Dietary Supplements; Role of Micronutrient Supplementation; Developing Countries; Developed Countries. Zinc: Physiology; Deficiency in Developing Countries, Intervention Studies.

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