Platelet Factor 4 Mediates Inflammation in Experimental Cerebral Malaria

Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
Cell host & microbe (Impact Factor: 12.33). 09/2008; 4(2):179-87. DOI: 10.1016/j.chom.2008.07.003
Source: PubMed


Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection in children. The pathogenesis of CM involves vascular inflammation, immune stimulation, and obstruction of cerebral capillaries. Platelets have a prominent role in both immune responses and vascular obstruction. We now demonstrate that the platelet-derived chemokine, platelet factor 4 (PF4)/CXCL4, promotes the development of experimental cerebral malaria (ECM). Plasmodium-infected red blood cells (RBCs) activated platelets independently of vascular effects, resulting in increased plasma PF4. PF4 or chemokine receptor CXCR3 null mice had less severe ECM, including decreased T cell recruitment to the brain, and platelet depletion or aspirin treatment reduced the development of ECM. We conclude that Plasmodium-infected RBCs can directly activate platelets, and platelet-derived PF4 then contributes to immune activation and T cell trafficking as part of the pathogenesis of ECM.

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    • "The zinc finger transcription factor KLF4 interacts with CREB and plays a wide range of roles, including the regulation of cell growth and differentiation [34]. Interestingly, evidence is emerging that KLF4 is involved in the pathophysiology of inflammatory diseases, including parasite infection [35–38]. We speculate that KLF4 plays a role in regulating ghrelin expression in response to helminth infection. "
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    • "). In addition, PF4 has been reported to worsen experimental cerebral pathology in mice, presumably mediated through the chemokine domain (Srivastava et al., 2008). Thus, we reasoned that synthetic small molecules capable of adopting amphipathic secondary structures analogous to a HDP could potentially reproduce the potent, selective antiparasitic activity of PF4 while improving tissue distribution and decreasing complications arising from chemokine signaling. "
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