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(American Journal of Pathology. 2005;166:295-302.)
© 2005 American Society for Investigative Pathology

ABCA1 Gene Deletion Protects against Cerebral Malaria

Potential Pathogenic Role of Microparticles in Neuropathology

Valéry Combes*, Nicolas Coltel*, Mélanie Alibert{dagger}, Miranda van Eck{ddagger}, Cécile Raymond{dagger}, Irène Juhan-Vague§, Georges Emile Grau* and Giovanna Chimini{dagger}

From the Laboratory of Immunopathology,* the Centre d’Immunologie de Marseille Luminy,{dagger} INSERM/Centre National de la Recherche Scientifique/Université de la Méditerranée, and the Haematology Laboratories,§ Faculty of Medicine, IFR48, Marseille, France; and the Division of Biopharmaceutics,{ddagger} Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands

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.




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