ABCA1 gene deletion protects against cerebral malaria: potential pathogenic role of microparticles in neuropathology.
The ATP-binding cassette transporter A1 (ABCA1) modulates the transbilayer distribution of phosphatidylserine at the outer leaflet of the plasma membrane. This external exposure of phosphatidylserine is a hallmark of microparticle production and is impaired in ABCA1(-/-) mice. In this study, we report about the complete resistance to cerebral malaria of these mice. On analysis of histological and systemic parameters we evidenced an impairment of cellular responses to Plasmodium berghei ANKA infection in ABCA1(-/-) mice, as shown by lower plasma tumor necrosis factor levels, a weaker up-regulation of endothelial adhesion molecules in brain microvessels, a reduced leukocyte sequestration, as well as an ablated platelet accumulation. Besides, the number and the procoagulant activity of microparticles were dramatically reduced in the plasma of ABCA1(-/-) compared to ABCA1(+/+) mice. Moreover, microparticles derived from Plasmodium berghei ANKA-infected ABCA1(+/+) mice induced a significant increase of tumor necrosis factor release by noninfected macrophages. In ABCA1(-/-) mice platelet and macrophage responses to vesiculation agonists were ablated and reduced, respectively. Altogether, by pointing out the ABCA1 transporter as a major element controlling cerebral malaria susceptibility, these data provide a novel insight into its pathophysiological mechanisms and are consistent with a pathogenic role of microparticles in this neurological syndrome.
Combes
Valéry
V
Laboratory of Immunopathology, Faculty of Medicine, IFR48, Université de la Méditerranée, 27, Bd Jean Moulin, F-13385 Marseille Cedex 05, France.
Coltel
Nicolas
N
Alibert
Mélanie
M
van Eck
Miranda
M
Raymond
Cécile
C
Juhan-Vague
Irène
I
Grau
Georges Emile
GE
Chimini
Giovanna
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010962:Plasmodium berghei; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D014409:Tumor Necrosis Factor-alpha