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Iron-Withholding Strategy in Innate Immunity

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Iron-Withholding Strategy in Innate Immunity ARTICLE IN PRESS Immunobiology 211 (2006) 295–314 www.elsevier.de/imbio REVIEW Iron-withholding strategy in innate immunity Sek Tong Onga, Jason Zhe Shan Hob, Bow Hoc,1, Jeak Ling Dinga,1,Ã aDepartment of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543 bFaculty of Medicine, Imperial College London, South Kensington, London SW7 2AZ, UK cDepartment of Microbiology, National University of Singapore, 5 Science Drive 2, Singapore 117597 Received 13 January 2006; accepted 14 February 2006 Abstract The knowledge of how organisms fight infections has largely been built upon the ability of host innate immune molecules to recognize microbial determinants. Although of overwhelming importance, pathogen recognition is but only one of the facets of innate immunity. A primitive yet effective antimicrobial mechanism which operates by depriving microbial organisms of their nutrients has been brought into the forefront of innate immunity once again. Such a tactic is commonly referred to as the iron-withholding strategy of innate immunity. In this review, we introduce various vertebrate iron-binding proteins and their invertebrate homologues, so as to impress upon readers an obscured arm of innate immune defense. An excellent comprehension of the mechanics of innate immunity paves the way for the possibility that novel antimicrobial therapeutics may emerge one day to overcome the prevalent antibiotic resistance in bacteria. r 2006 Elsevier GmbH. All rights reserved. Keywords: Innate immunity; Iron sequestration; Ferritin; Hepcidin; Lipocalin; Nramp; Transferrin Contents Introduction . 296 Iron as a double-edged sword in biological systems . 296 How is iron involved in innate immunity? . 297 Advances in vertebrate host innate immune defense: the iron-withholding strategy . 298 Lipocalin – sequestration of iron-laden siderophores. 298 Hepcidin – a mediator of intracellular iron efflux . 300 Nramp (natural resistance-associated macrophage protein) – for effective macrophage defense mechanism . 302 Vertebrate transferrin family – an acute-phase Fe3+-binding protein . 303 Vertebrate ferritins – iron storage and detoxification. 303 Homologues of vertebrate iron-binding proteins are explicitly represented in invertebrates . 304 Abbreviations: DMT1, divalent cation transporter 1; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharides; Nramp, natural resistance- associated macrophage protein; PAMPs, pathogen-associated molecular patterns; PRRs, pattern recognition receptors; SPI2, Salmonella pathogenicity island 2; TNF-a, tumor necrosis factor-a ÃCorresponding author. Tel.: +65 68742776; fax: +65 67792486. E-mail address: [email protected] (J.L. Ding). 1Co-senior authors. 0171-2985/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.imbio.2006.02.004 ARTICLE IN PRESS 296 S.T. Ong et al. / Immunobiology 211 (2006) 295–314 Invertebrate transferrin . 304 Invertebrate ferritins . 304 How iron-binding proteins may influence apoptosis. 305 Future perspectives. 308 Acknowledgements . 308 References . 308 Introduction carrier during the evolution of early life (Andrews et al., 2003). Iron plays an indispensable role in various The biological explanation to relate the pathogenesis physiological processes, such as photosynthesis, nitro- of anemia of inflammation and the regulation of iron gen fixation, methanogenesis, hydrogen production and absorption and distribution has been a challenge in consumption, respiration, the trichloroacetic acid cycle, classical hematology (Ganz, 2003). A well-known com- oxygen transport, gene regulation and DNA biosynth- ponent of innate immunity uses pattern recognition esis. The incorporation of iron into proteins allows its receptors (PRRs) to recognize pathogen-associated local environment to be regulated such that iron can molecular patterns (PAMPs) (Medzhitov and Janeway, adopt the necessary redox potential (À300 to 1997) in the detection and eradication of pathogens. The +700 mV), geometry and spin state for realization of PRRs serve as frontline surveillance molecules and may its prescribed functions (Andrews et al., 2003). trigger downstream processes to accelerate pathogen Unfortunately, with the appearance of oxygen on clearance. As the wealth of knowledge has accumulated earth approximately 2.2–2.7 billion years ago, two in pathogen recognition, another component of innate major problems arose. One was the production of toxic immunity, the iron-withholding strategy, has gradually oxygen species and the other, a drastic decrease in iron caught the attention of immunologists. To convey the availability (Touati, 2000). In its reduced ferrous form, excitement of advances on iron regulation and innate iron potentiates oxygen toxicity by converting the less immunity, we shall explore various iron-binding pro- reactive hydrogen peroxide to the more reactive oxygen teins in the vertebrates and invertebrates to develop an species, hydroxyl radical and ferryl iron, via the Fenton appreciation of the iron-withholding strategy that reaction (Fig. 1). Conversely, superoxide favors the deserves equal recognition for its role in ensuring the Fenton reaction by releasing iron from iron-containing continual survival of organisms against infections. molecules. It is widely accepted that tight regulation of iron assimilation prevents an excess of free intracellular iron that could lead to oxidative stress. Iron as a double-edged sword in biological Iron bioavailability has also been associated with systems sepsis, which has been a challenge to humans and it has steadily worsened in recent years. In the United States Iron is an abundant metal, being the fourth most alone, there are 500,000 incidents each year with a plentiful element in the earth’s crust. As a transition death rate of 35–65% (Dellinger et al., 1997; Bone et al., metal, it exists mainly in one of the two readily reversible 1997). Amongst the numerous complex interactions redox states: the reduced Fe2+ ferrous form and the between host and pathogen, one common and essential oxidized Fe3+ ferric form. Depending on its ligand factor is the ability to invade and multiply successfully environment, both ferrous and ferric forms can adopt within host tissues. Proliferation of a pathogen is critical different spin states. As a result of these properties, iron to its establishing an infection and this facilitates the is an extremely attractive prosthetic component for pathogen to produce the full arsenal of virulence incorporation into proteins as a biocatalyst or electron determinants required for pathogenicity (Bullen et al., - 3 + 2+ O2 + Fe O2+ Fe [ 1 ] 2+ • - 3+ H2O2+ Fe OH + OH + Fe (Fenton reaction) [ 2 ] Fig. 1. The Fenton reaction. In the first reaction, the ferric ion converts a superoxide anion to oxygen, as it becomes reduced in the process. In the next step, the ferrous ion converts hydrogen peroxide into hydroxyl radical and hydroxyl anion. The hydroxyl radical is highly reactive and may react with host biological macromolecules (Moody and Hassan, 1982; Cerutti, 1985). ARTICLE IN PRESS S.T. Ong et al. / Immunobiology 211 (2006) 295–314 297 2000). The availability of iron in the host environment tenance of low plasma iron may be achieved in the host and its effects on bacterial growth is one of the best- would be illustrated with various iron-binding proteins studied aspects in pathogenicity (Schade and Caroline, that the host employs. 1946; Weinberg, 2005). Humans are equipped with a well-developed natural resistance against bacterial in- fection. Currently, some of the understood mechanisms How is iron involved in innate immunity? involved are the antibacterial properties of tissue fluids and the phagocytic abilities of cells (Bullen et al., 2000). Traditionally, the innate immune system is represented However, research has revealed that these mechanisms by a frontline defense that targets microbial pathogens require a virtually iron-free environment for proper by recognizing molecular structures that are shared by function (Ward and Bullen, 1999). In normal human large groups of pathogens, the PAMPs via PRRs. The plasma, the extremely high-affinity constant for Fe3+ PAMPs are conserved products of microbial metabo- (10À36 M) and the unsaturated state of the iron-binding lism, which are essential for the survival or pathogenicity protein, transferrin, ensure that the amount of free ferric of the microorganisms (Medzhitov and Janeway, 1997). iron is only 10À18 M(Bullen et al., 1978). In vivo, Examples of PAMPs include lipopolysaccharides (LPS) bacterial growth is inhibited by strong bactericidal and of Gram-negative bacteria, lipoteichoic acids of Gram- bacteriostatic mechanisms in the plasma. These include positive bacteria and the mannans of yeasts/fungi. A key unsaturated transferrin, antibody and complement feature of these microbial patterns is their polysaccharide components, which function in the virtual absence of chains that vary in length and carbohydrate composition freely available iron. Intracellularly, iron is essential for (Franc and White, 2000), to which the hosts have neutrophil myeloperoxidases involved in bactericidal evolved different PRRs to recognize and differentiate activity (Erickson et al., 2000). (Zhu et al. and Ng et al. personal communications). Even though freely available iron in normal body The invertebrates have a defense system centered on fluids is virtually absent, pathogenic bacteria are able to both cellular and humoral immune response. The multiply successfully
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