Heme oxygenase-1 as a therapeutic target in anti-HLA antibody-triggered transplant vasculopathy
Final Report Abstract
The antioxidant inducible enzyme heme oxygenase (HO)-1 has major anti-inflammatory effects mediated by metabolic degradation of pro-inflammatory heme and production of carbon monoxide (CO) and biliverdin. In addition, overexpression of HO-1 has been shown to be beneficial in various experimental models of solid organ transplantation. The goal of this project was to gain a better understanding of the specific role of HO-1 and its substrate heme in inflammatory processes involved in organ transplantation and ischemia-reperfusion injury (IRI) with a particular focus on the endothelium and dedicated immune cells. Because anti-human leukocyte antigen (HLA) antibody-mediated rejection is a major limiting factor for graft survival after solid organ transplantation, the role of HO-1 was determined in cell culture models of anti-HLA I and II antibody interaction with human endothelial cells. Specifically, targeted induction of HO-1 was able to counteract inflammatory activation of endothelial cells in response to treatment with anti-HLA class I antibodies (1). In contrast, HO-1 did not interfere with the effects of anti-HLA II antibody ligation to endothelial cells. Endothelial binding of anti-HLA II antibodies led to necrotic cell death via a defined lysosomal membrane permeabilization-mediated pathway involving the generation of mitochondrial reactive oxygen species (2). We also examined the role of the heme/ HO-1-system for inflammatory processes related to transplantation and IRI in various experimental murine disease models. It was demonstrated in a renal IRI model with subsequent fibrosis that anti-inflammatory protective effects of the complement 5a receptor 2, a key receptor for inflammatory kidney diseases, was mediated via a HO-1-dependent mechanism. This pathway involved the anti-inflammatory cytokine interleukin-10 and activation of the AKT signaling cascade (3). In a model of unilateral renal IRI, local release of free heme in kidney was associated with a marked inflammatory response and up-regulation of HO-1. In this model, pro-inflammatory effects of free heme were attenuated by administration of the heme-binding protein human serum albumin suggesting that scavenging of prooxidant free heme might be a therapeutic approach for treating renal IRI and other IRI-mediated inflammatory conditions associated with heme toxicity (4). Along this line, we also showed that human α1-antitrypsin, an acute-phase serum protein with high heme-binding affinity, counteracted inflammatory activation and cytotoxicity of free heme in human endothelial cells and neutrophils. Notably, α1-antitrypsin mediated anti-inflammatory effects via a mechanism that was different from that of other heme-binding proteins including hemopexin and serum albumin (5, 6). In conclusion, the findings of this project contribute to a better understanding of the immuno-modulatory role of the heme/ HO-1 system in inflammatory processes associated with solid organ transplantation and IRI. Further studies will help to improve diagnostic approaches and anti-inflammatory therapies in these conditions.
Publications
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2015. Heme Oxygenase-1 Inhibits HLA Class I Antibody-Dependent Endothelial Cell Activation. PLoS One 10: e0145306
Zilian, E., H. Saragih, V. Vijayan, O. Hiller, C. Figueiredo, A. Aljabri, R. Blasczyk, G. Theilmeier, J. U. Becker, J. Larmann, and S. Immenschuh
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2017. A New Immunomodulatory Role for Peroxisomes in Macrophages Activated by the TLR4 Ligand Lipopolysaccharide. J. Immunol. 198: 2414-2425
Vijayan, V., T. Srinu, S. Karnati, V. Garikapati, M. Linke, L. Kamalyan, S. R. Mali, K. Sudan, A. Kollas, T. Schmid, S. Schulz, B. Spengler, T. Weichhart, S. Immenschuh, and E. Baumgart-Vogt
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2018. Enhanced activation of interleukin-10, heme oxygenase-1, and AKT in C5aR2-deficient mice is associated with protection from ischemia reperfusion injury-induced inflammation and fibrosis. Kidney Int. 94: 741-755
Thorenz, A., K. Derlin, C. Schroder, L. Dressler, V. Vijayan, P. Pradhan, S. Immenschuh, A. Jorns, F. Echtermeyer, C. Herzog, R. Chen, S. Rong, J. H. Brasen, C. van Kooten, T. Kirsch, C. Klemann, M. Meier, A. Klos, H. Haller, B. Hensen, and F. Gueler
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2019. HLA class II antibodies induce necrotic cell death in human endothelial cells via a lysosomal membrane permeabilization-mediated pathway. Cell Death Dis. 10: 235
Aljabri, A., V. Vijayan, M. Stankov, C. Nikolin, C. Figueiredo, R. Blasczyk, J. U. Becker, A. Linkermann, and S. Immenschuh
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2019. Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis. Redox Biol. 22: 101147
Vijayan, V., P. Pradhan, L. Braud, H. R. Fuchs, F. Gueler, R. Motterlini, R. Foresti, and S. Immenschuh
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2019. Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury. Front. Immunol. 10: 2975
Wang, L., V. Vijayan, M. S. Jang, A. Thorenz, R. Greite, S. Rong, R. Chen, N. Shushakova, I. Tudorache, K. Derlin, P. Pradhan, K. Madyaningrana, N. Madrahimov, J. H. Brasen, R. Lichtinghagen, C. van Kooten, M. Huber-Lang, H. Haller, S. Immenschuh, and F. Gueler
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2019. TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages. Free Radic. Biol. Med. 137: 131-142
Sudan, K., V. Vijayan, K. Madyaningrana, F. Gueler, K. Igarashi, R. Foresti, R. Motterlini, and S. Immenschuh
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2020. Ischemia Reperfusion Injury Triggers CXCL13 Release and B-Cell Recruitment After Allogenic Kidney Transplantation. Front. Immunol. 11: 1204
Kreimann, K., M. S. Jang, S. Rong, R. Greite, S. von Vietinghoff, R. Schmitt, J. H. Brasen, L. Schiffer, J. Gerstenberg, V. Vijayan, O. Dittrich-Breiholz, L. Wang, C. M. Karsten, W. Gwinner, H. Haller, S. Immenschuh, and F. Gueler
