Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles. - Université de Lille Accéder directement au contenu
Article Dans Une Revue JCI Insight Année : 2018

Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles.

Nathan Brinkman
  • Fonction : Auteur
Thomas Gentinetta
  • Fonction : Auteur
Monika Edler
  • Fonction : Auteur
Sara Petrillo
  • Fonction : Auteur
Emanuela Tolosano
  • Fonction : Auteur
Sylvia Miescher
  • Fonction : Auteur
Sylvain Le Jeune
  • Fonction : Auteur
Marion Rabant
  • Fonction : Auteur

Résumé

In hemolytic diseases, such as sickle cell disease (SCD), intravascular hemolysis results in the release of hemoglobin, heme, and heme-loaded membrane microvesicles in the bloodstream. Intravascular hemolysis is thus associated with inflammation and organ injury. Complement system can be activated by heme in vitro. We investigated the mechanisms by which hemolysis and red blood cell (RBC) degradation products trigger complement activation in vivo. In kidney biopsies of SCD nephropathy patients and a mouse model with SCD, we detected tissue deposits of complement C3 and C5b-9. Moreover, drug-induced intravascular hemolysis or injection of heme or hemoglobin in mice triggered C3 deposition, primarily in kidneys. Renal injury markers (Kim-1, NGAL) were attenuated in C3-/- hemolytic mice. RBC degradation products, such as heme-loaded microvesicles and heme, induced alternative and terminal complement pathway activation in sera and on endothelial surfaces, in contrast to hemoglobin. Heme triggered rapid P selectin, C3aR, and C5aR expression and downregulated CD46 on endothelial cells. Importantly, complement deposition was attenuated in vivo and in vitro by heme scavenger hemopexin. In conclusion, we demonstrate that intravascular hemolysis triggers complement activation in vivo, encouraging further studies on its role in SCD nephropathy. Conversely, heme inhibition using hemopexin may provide a novel therapeutic opportunity to limit complement activation in hemolytic diseases.

Dates et versions

hal-04432315 , version 1 (01-02-2024)

Identifiants

Citer

S Merle Nicolas, Anne Grunenwald, Helena Rajaratnam, Viviane Gnemmi, Marie Frimat, et al.. Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles.. JCI Insight, 2018, JCI Insight, 3, ⟨10.1172/jci.insight.96910⟩. ⟨hal-04432315⟩
7 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More