Immunopathological consequences of the loss of engulfment genes: the case of ABCA1.
Programmed cell death plays a crucial role in the maintenance of cell homeostasis. An initial, effector phase leads to the generation of apoptotic corpses and is closely followed by a swift clearance by professional or amateur phagocytes. Several aspects distinguish this latter process of engulfment of dying cells from the classical forms of phagocytosis. They concern all aspects of the process from the recognition of the prey to the final outcome, i.e. immunological silence. The engulfment of dead cells is a process highly conserved through evolution and it has been studied in parallel in two systems, mammalian cells and the nematode C. elegans. ABCA1 and its ortholog CED-7 in the nematode are key players of engulfment. Their mode of action is somehow original in the panorama of engulfment receptors since they act as lipid transporters. While in the worm the loss of CED-7 has phenotypic consequences exclusively on engulfment, in the mouse the deletion of ABCA1 by homologous recombination has highlighted broad consequences on macrophage biology. Among those we will discuss here the aberrant responses of ABCA1-/- mice to Plasmodium berghei ANKA infection, concerning in particular the development of cerebral malaria (CM), a cytokine-induced immunopathology. This syndrome involves a central role of monocytes and, as shown recently, high levels of circulating microparticles. It was found that ABCA1 loss completely protects against CM and its associated mortality. This observation, together with the demonstration of quantitative and functional modifications of microparticles, suggests that microparticles may be involved in CM pathogenesis. The ABCA1 transporter thus appears to control susceptibility to CM, thereby providing new insights in its pathophysiological mechanisms and potential new therapeutic avenues.
Grau
Georges E
GE
Immunopathology Group, Faculté de Médecine, IFR48, 27, boulevard Jean Moulin, F-13385 Marseille Cedex 5, France.
Chimini
Giovanna
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D019143:Evolution, Molecular; D017353:Gene Deletion; D006801:Humans; D008055:Lipids / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D016779:Malaria, Cerebral / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D008322:Mammals / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008954:Models, Biological; D009000:Monocytes / Q000502:physiology; D010316:Particle Size; D010587:Phagocytosis / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D010962:Plasmodium berghei; D011956:Receptors, Cell Surface / Q000502:physiology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001324:Autoantigens; C112887:CED-7 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008055:Lipids; D011956:Receptors, Cell Surface