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Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles
Nicolas S. Merle, … , Olivier P. Blanc-Brude, Lubka T. Roumenina
Nicolas S. Merle, … , Olivier P. Blanc-Brude, Lubka T. Roumenina
Published June 21, 2018
Citation Information: JCI Insight. 2018;3(12):e96910. https://doi.org/10.1172/jci.insight.96910.
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Research Article Inflammation Vascular biology

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

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Abstract

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.

Authors

Nicolas S. Merle, Anne Grunenwald, Helena Rajaratnam, Viviane Gnemmi, Marie Frimat, Marie-Lucile Figueres, Samantha Knockaert, Sanah Bouzekri, Dominique Charue, Remi Noe, Tania Robe-Rybkine, Marie Le-Hoang, Nathan Brinkman, Thomas Gentinetta, Monika Edler, Sara Petrillo, Emanuela Tolosano, Sylvia Miescher, Sylvain Le Jeune, Pascal Houillier, Sophie Chauvet, Marion Rabant, Jordan D. Dimitrov, Veronique Fremeaux-Bacchi, Olivier P. Blanc-Brude, Lubka T. Roumenina

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Figure 1

Patients suffering from SCD nephropathy and SCD mice have complement deposition within kidneys.

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Patients suffering from SCD nephropathy and SCD mice have complement dep...
(A) C3 fragment staining (false color green) and (B) C9 staining (brown) of kidney biopsies of patients with SCD nephropathy, performed by immunofluorescence of frozen tissue and immunohistochemistry of paraffin-embedded tissues, respectively. A normal protocol kidney allograft biopsy performed at 3 months was used as a negative control and a biopsy of a patient with acute humoral rejection was used as a positive control for the staining. (C) C3b/iC3b (false color green) and C5b-9 (false color red) staining of kidney sections of HbAA and HbSS mice. Quantification of the C3 and C5b-9 staining in HbSS (n ≥ 7 mice per group) and HbAA (n ≥ 4 mice per group) mouse kidney glomeruli. (D) C3b/iC3b (false color green) and C5b-9 (false color red) staining of kidney sections of SAD mice and WT littermates. Quantification of the C3 and C5b-9 staining in kidney glomeruli (n ≥ 7 mice per group). (E) Double staining of SAD and HbSS mouse kidney sections for C3b/iC3b (false color green) and endothelial marker CD31 (false color red). The merge image indicates colocalization in orange. One glomerulus was focused on. *P < 0.05; **P < 0.005; ***P < 0.001, Mann-Whitney test. Values are shown as box plots with median and minimum/maximum points. Scale bar: 50 μm. Original magnification, ×26.
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