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P-selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/heme-dependent manner.

Merle, Nicolas S; Paule, Romain; Leon, Juliette; Daugan, Marie; Robe-Rybkine, Tania; Poillerat, Victoria; Torset, Carine; Frémeaux-Bacchi, Véronique; Dimitrov, Jordan D; Roumenina, Lubka T.
Proc Natl Acad Sci U S A; 116(13): 6280-6285, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850533
Hemolytic diseases are frequently linked to multiorgan failure subsequent to vascular damage. Deciphering the mechanisms leading to organ injury upon hemolytic event could bring out therapeutic approaches. Complement system activation occurs in hemolytic disorders, such as sickle cell disease, but the pathological relevance and the acquisition of a complement-activating phenotype during hemolysis remain unclear. Here we found that intravascular hemolysis, induced by injection of phenylhydrazine, resulted in increased alanine aminotransferase plasma levels and NGAL expression. This liver damage was at least in part complement-dependent, since it was attenuated in complement C3-/- mice and by injection of C5-blocking antibody. We evidenced C3 activation fragments' deposits on liver endothelium in mice with intravascular hemolysis or injected with heme as well as on cultured human endothelial cells (EC) exposed to heme. This process was mediated by TLR4 signaling, as revealed by pharmacological blockade and TLR4 deficiency in mice. Mechanistically, TLR4-dependent surface expression of P-selectin triggered an unconventional mechanism of complement activation by noncovalent anchoring of C3 activation fragments, including the typical fluid-phase C3(H2O), measured by surface plasmon resonance and flow cytometry. P-selectin blockade by an antibody prevented complement deposits and attenuated the liver stress response, measured by NGAL expression, in the hemolytic mice. In conclusion, these results revealed the critical impact of the triad TLR4/P-selectin/complement in the liver damage and its relevance for hemolytic diseases. We anticipate that blockade of TLR4, P-selectin, or the complement system could prevent liver injury in hemolytic diseases like sickle cell disease.
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