Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1

Olivia May, Nicolas S Merle, Anne Grunenwald, Viviane Gnemmi, Juliette Leon, Cloé Payet, Tania Robe-Rybkine, Romain Paule, Florian Delguste, Simon C Satchell, Peter W Mathieson, Marc Hazzan, Eric Boulanger, Jordan D Dimitrov, Veronique Fremeaux-Bacchi, Marie Frimat, Lubka T Roumenina

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Abstract

Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in in vitro and in vivo models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, in vitro and in vivo, compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4-known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions.

Original languageEnglish
Article number3008
Number of pages17
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 20 Dec 2018

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    May, O., Merle, N. S., Grunenwald, A., Gnemmi, V., Leon, J., Payet, C., Robe-Rybkine, T., Paule, R., Delguste, F., Satchell, S. C., Mathieson, P. W., Hazzan, M., Boulanger, E., Dimitrov, J. D., Fremeaux-Bacchi, V., Frimat, M., & Roumenina, L. T. (2018). Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1. Frontiers in Immunology, 9, [3008]. https://doi.org/10.3389/fimmu.2018.03008