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The Journal of Immunology, 2004, 172: 3101-3110.
Copyright © 2004 by The American Association of Immunologists

Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection 1

Maritza Jaramillo*, Isabelle Plante*, Nathalie Ouellet*, Karen Vandal*, Philippe A. Tessier* and Martin Olivier2,*,{dagger}

* Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Quebec, Pavillon Centre Hospitalier de l’Université Laval, and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Ste-Foy, Quebec, Canada; and {dagger} Research Institute of the McGill University Health Centre, Centre for the Study of Host Resistance, Departments of Medicine, Microbiology, and Immunology, McGill University, Montreal, Quebec, Canada

During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity. Even if their role as activators of the host immune response has been studied, the direct contribution of hemozoin (HZ), a parasite metabolite, to such a strong induction is not fully understood. Previous in vitro studies demonstrated that both Plasmodium falciparum HZ and synthetic HZ (sHZ), {beta}-hematin, induce macrophage/monocyte chemokine and proinflammatory cytokine secretion. In the present study, we investigated the proinflammatory properties of sHZ in vivo. To this end, increasing doses of sHZ were injected either i.v. or into an air pouch generated on the dorsum of BALB/c mice over a 24-h period. Our results showed that sHZ is a strong modulator of leukocyte recruitment and more specifically of neutrophil and monocyte populations. In addition, evaluation of chemokine and cytokine mRNA and protein expression revealed that sHZ induces the expression of chemokines, macrophage-inflammatory protein (MIP)-1{alpha}/CCL3, MIP-1{beta}/CCL4, MIP-2/CXCL2, and monocyte chemoattractant protein-1/CCL2; chemokine receptors, CCR1, CCR2, CCR5, CXCR2, and CXCR4; cytokines, IL-1{beta} and IL-6; and myeloid-related proteins, S100A8, S100A9, and S100A8/A9, in the air pouch exudates. Of interest, chemokine and cytokine mRNA up-regulation were also detected in the liver of i.v. sHZ-injected mice. In conclusion, our study demonstrates that sHZ is a potent proinflammatory agent in vivo, which could contribute to the immunopathology related to malaria.




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