title: Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement.
abstract: OBJECTIVE
  Transfusion of aged blood has been associated with increased morbidity and mortality in critically ill patients. During storage, erythrocytes release increasing numbers of microvesicles (red blood cell-derived microvesicles [RBC-MV]). We hypothesized that RBC-MV mediate some of the deleterious effects of aged blood transfusions.
  
  
  RESULTS
  We established a murine transfusion model using RBC-MV purified from aged mouse erythrocytes. Injection of RBC-MV into healthy mice had no effect. However, they aggravated pulmonary leukocyte sequestration and peripheral blood leukopenia induced by lipopolysaccharides. Lipopolysaccharide-induced proinflammatory cytokines were significantly increased in plasma after RBC-MV injection. These effects were not seen in C5aR-deficient mice. In vitro, RBC-MV bound C3 fragments after incubation with plasma but failed to bind immunoglobulins, C1q, or mannose-binding lectin. Preventing thrombin generation inhibited complement activation in vitro and in vivo and reversed the proinflammatory effects of RBC-MV in lipopolysaccharide-primed mice. Finally, the RBC-MV-induced phenotype was recapitulated using phosphatidylserine-expressing liposomes, suggesting that surface expression of phosphatidylserine by RBC-MV was mechanistically involved.
  
  
  CONCLUSIONS
  These results point toward a thrombin-dependent mechanism of complement activation by RBC-MV independent of the classical, lectin, or alternative pathway. Besides identifying RBC-MV as potential mediators of transfusion-related morbidity, our findings may be relevant for other inflammatory disorders involving intravascular microvesicle release, for example, sickle cell disease or thrombotic microangiopathy.
authors: From the Department of Biomedicine (D.Z., A.C., J.S.), Department of Transplantation Immunology and Nephrology (D.Z.), and Department of Medicine (D.Z., J.S.), University Hospital Basel, Basel University, Basel, Switzerland.
authors: Daniel
authors: D
authors: Zecher
authors: Arun
authors: A
authors: Cumpelik
authors: Jürg A
authors: JA
authors: Schifferli
mesh_terms: D000818:Animals; D055252:Cell-Derived Microparticles / Q000276:immunology* / Q000378:metabolism; D003167:Complement Activation; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism; D017707:Erythrocyte Transfusion / Q000009:adverse effects*; D004912:Erythrocytes / Q000276:immunology* / Q000378:metabolism; D005838:Genotype; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000276:immunology*; D007970:Leukopenia / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides; D008081:Liposomes; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D020556:Neutrophil Infiltration; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D010718:Phosphatidylserines / Q000276:immunology / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics; D013917:Thrombin / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D003176:Complement C3; D008070:Lipopolysaccharides; D008081:Liposomes; D010446:Peptide Fragments; D010718:Phosphatidylserines; D044087:Receptor, Anaphylatoxin C5a; C482199:lipopolysaccharide, E coli O55-B5; D013917:Thrombin
keywords: blood coagulation; blood component transfusion; cell-derived microparticles; complement system proteins; inflammation