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* Research Institute of McGill University Health Center, Center for the Study of Host Resistance, Departments of Medicine, Microbiology, and Immunology, McGill University, Montréal, Québec, Canada; and
Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Pavillon Centre Hospitalier de l’Université Laval, and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Ste-Foy, Québec, Canada
Chemokine production has been associated with the immunopathology related to malaria. Previous findings indicated that hemozoin (HZ), a parasite metabolite released during schizogeny, might be an important source of these proinflammatory mediators. In this study we investigated the molecular mechanisms underlying HZ-inducible macrophage (M
) chemokine mRNA expression. We found that both Plasmodium falciparum HZ and synthetic HZ increase mRNA levels of various chemokine transcripts (MIP-1
/CCL3, MIP-1
/CCL4, MIP-2/CXCL2, and MCP-1/CCL2) in murine B10R M. The cellular response to HZ involved ERK1/2 phosphorylation, NF-
B activation, reactive oxygen species (ROS) generation, and ROS-dependent protein-tyrosine phosphatase down-regulation. Selective inhibition of either IB or the ERK1/2 pathway abolished both NF-B activation and chemokine up-regulation. Similarly, blockage of HZ-inducible M ROS with superoxide dismutase suppressed chemokine induction, strongly reduced NF-B activation, and restored HZ-mediated M protein-tyrosine phosphatase inactivation. In contrast, superoxide dismutase had no effect on EKR1/2 phosphorylation by HZ. Collectively, these data indicate that HZ triggers ROS-dependent and -independent signals, leading to increased chemokine mRNA expression in M. Overall, our findings may help to better understand the molecular mechanisms through which parasite components, such as HZ, modulate the immune response during malaria infection.
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