Platelet factor 4 mediates inflammation in experimental cerebral malaria.
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.
Srivastava
Kalyan
K
Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
Cockburn
Ian A
IA
Swaim
AnneMarie
A
Thompson
Laura E
LE
Tripathi
Abhai
A
Fletcher
Craig A
CA
Shirk
Erin M
EM
Sun
Henry
H
Kowalska
M Anna
MA
Fox-Talbot
Karen
K
Sullivan
David
D
Zavala
Fidel
F
Morrell
Craig N
CN
D000818:Animals; D001921:Brain / Q000276:immunology / Q000469:parasitology; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D054884:Host-Pathogen Interactions; D006801:Humans; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010963:Plasmodium falciparum / Q000276:immunology / Q000502:physiology*; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000235:genetics / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D010978:Platelet Factor 4