Hemozoin induces macrophage chemokine expression through oxidative stress-dependent and -independent mechanisms.
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 (Mphi) chemokine mRNA expression. We found that both Plasmodium falciparum HZ and synthetic HZ increase mRNA levels of various chemokine transcripts (MIP-1alpha/CCL3, MIP-1beta/CCL4, MIP-2/CXCL2, and MCP-1/CCL2) in murine B10R Mphi. The cellular response to HZ involved ERK1/2 phosphorylation, NF-kappaB activation, reactive oxygen species (ROS) generation, and ROS-dependent protein-tyrosine phosphatase down-regulation. Selective inhibition of either IkappaBalpha or the ERK1/2 pathway abolished both NF-kappaB activation and chemokine up-regulation. Similarly, blockage of HZ-inducible Mphi ROS with superoxide dismutase suppressed chemokine induction, strongly reduced NF-kappaB activation, and restored HZ-mediated Mphi 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 Mphi. 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.
Jaramillo
Maritza
M
Research Institute of McGill University Health Center, Center for the Study of Host Resistance, Departments of Medicine, Microbiology, and Immunology, McGill University, 3775 University Street, Montréal, Québec, Canada H3A 2B4.
Godbout
Marianne
M
Olivier
Martin
M
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006420:Hemeproteins / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology*; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism
D018925:Chemokines; D004791:Enzyme Inhibitors; D006420:Hemeproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C020753:hemozoin; D048049:Extracellular Signal-Regulated MAP Kinases; D017027:Protein Tyrosine Phosphatases