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The basis of the immunomodulatory activity of malaria pigment (hemozoin)

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Abstract

The most common and deadly form of the malaria parasite, Plasmodium falciparum, is responsible for 1.5–2.7 million deaths and 300–500 million acute illnesses annually [Bremen in J. Trop. Med. Hyg. 64:1–11 (2001); World Health Organization (2002)]. Hemozoin, the biomineral formed to detoxify the free heme produced during parasitic hemoglobin catabolism, has long been suspected of contributing to the pathological immunodeficiencies that occur during malarial infection. While there is a growing consensus in the literature that native hemozoin maintains immunosuppressive activity, there is considerable controversy over the reactivity of the synthetic form, β-hematin (BH). Given the emerging importance of hemozoin in modulating a host immune response to malarial infection, a careful examination of the effects of the constitutive components of the malaria pigment on macrophage response has been made in order to clarify the understanding of this process. Herein, we present evidence that BH alone is unable to inhibit stimulation of NADPH oxidase and inducible nitric oxide synthase, the key enzymes involved in oxidative burst, and is sensitive to the microbicidal agents of these enzymes both in vitro and in vivo. Further, by systematically examining each of the malaria pigment’s components, we were able to dissect their impact on the immune reactivity of a macrophage model cell line. Reactions between BH and red blood cell (RBC) ghosts effectively reconstituted the observed immunomodulatory reactivity of native hemozoin. Together, these results suggest that the interaction between hemozoin and the RBC lipids results in the generation of toxic products and that these products are responsible for disrupting macrophage function in vivo.

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Abbreviations

BH:

β-Hematin

DCF-DA:

Dichlorofluorescein diacetate

DeaNO:

Diethylamine/nitric oxide sodium complex

DMSO:

Dimethyl sulfoxide

Fe(III)PPIX:

Ferric protoporphyrin IX

FTIR:

Fourier transform IR

15-HETE:

15-S-Hydroxyeicosatetraenioc acid

Hepes:

N-(2-Hydroxyethyl)piperazine-N′-ethanesulfonic acid

HNE:

4-Hydroxy-2-nonenal

iNOS:

Inducible nitric oxide synthase

LPS:

Lippopolysaccharide

NED:

N-(1-Naphthyl)ethylenediamine

PBS:

Phosphate-buffered saline

Pipes:

Piperazine-1,4-bis(2-ethanesulfonic acid)

PMA:

Phorbol-12-myristate-13-acetate

RBC:

Red blood cell

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

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Acknowledgements

D.W.W. thanks NIH for financial support through NIH (NIAID) grant 1R03AI060827. Confocal images using a Zeiss LSM 510 Meta inverted confocal microscope were performed in part through the use of the VUMC Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, HD15052, DK59637, and EY08126). The Wright group would also like to thank the laboratory of Virginia Shepherd for access to cell lines and experimental equipment, expert advice and helpful discussions during this project.

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Authors and Affiliations

  1. Department of Chemistry, Vanderbilt University, Station B. 351822, Nashville, TN, 37235, USA

    Clare K. Carney, Alexandra C. Schrimpe, Kristin Halfpenny, Reese S. Harry, Crystal M. Miller, Malgorzata Broncel, Sarah L. Sewell, Jacob E. Schaff, Ravinder Deol, Melissa D. Carter & David W. Wright

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  1. Clare K. Carney
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Correspondence to David W. Wright.

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Carney, C.K., Schrimpe, A.C., Halfpenny, K. et al. The basis of the immunomodulatory activity of malaria pigment (hemozoin). J Biol Inorg Chem 11, 917–929 (2006). https://doi.org/10.1007/s00775-006-0147-0

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