title: Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome.
abstract: Atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormalities of the complement system leading to alternative pathway (AP) overactivation and by glomerular endothelial damage, thrombosis, and mechanical hemolysis. Mutations per se are not sufficient to induce aHUS, and nonspecific primary triggers are required for disease manifestation. We investigated whether hemolysis-derived heme contributes to aHUS pathogenesis. We confirmed that heme activates complement AP in normal human serum, releasing C3a, C5a, and sC5b9. We demonstrated that heme-exposed endothelial cells also activate the AP, resulting in cell-bound C3 and C5b9. This was exacerbated in aHUS by genetic abnormalities associated with AP overactivation. Heme interacted with C3 close to the thioester bond, induced homophilic C3 complexes, and promoted formation of an overactive C3/C5 convertase. Heme induced decreased membrane cofactor protein (MCP) and decay-accelerating factor (DAF) expression on endothelial cells, giving Factor H (FH) a major role in complement regulation. Finally, heme promoted a rapid exocytosis of Weibel-Palade bodies, with membrane expression of P-selectin known to bind C3b and trigger the AP, and the release of the prothrombotic von Willebrand factor. These results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS.
authors.affiliation: INSERM, Unite Mixte de Recherche en Sante 872, Cordeliers Research Center, 15 rue de l'Ecole de Medecine, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Frimat
authors.forename: Fanny
authors.initials: F
authors.lastname: Tabarin
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Dimitrov
authors.forename: Caroline
authors.initials: C
authors.lastname: Poitou
authors.forename: Lise
authors.initials: L
authors.lastname: Halbwachs-Mecarelli
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006418:Heme / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D019007:P-Selectin / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology
chemical_list: D003176:Complement C3; D019007:P-Selectin; D006418:Heme; D003179:Complement C3b; D050577:Complement C3-C5 Convertases