Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling
Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289744/full |
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| author | Guido Moll Guido Moll Christian Luecht Michael Adu Gyamfi Dennyson L. M. da Fonseca Pinchao Wang Hongfan Zhao Zexian Gong Lei Chen Muhamad Imtiaz Ashraf Harald Heidecke Alexander Maximilian Hackel Duska Dragun Klemens Budde Olaf Penack Olaf Penack Gabriela Riemekasten Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Janusz Witowski Janusz Witowski Rusan Catar |
| author_facet | Guido Moll Guido Moll Christian Luecht Michael Adu Gyamfi Dennyson L. M. da Fonseca Pinchao Wang Hongfan Zhao Zexian Gong Lei Chen Muhamad Imtiaz Ashraf Harald Heidecke Alexander Maximilian Hackel Duska Dragun Klemens Budde Olaf Penack Olaf Penack Gabriela Riemekasten Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Janusz Witowski Janusz Witowski Rusan Catar |
| author_sort | Guido Moll |
| collection | DOAJ |
| description | Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses. |
| first_indexed | 2024-03-11T14:51:27Z |
| format | Article |
| id | doaj.art-0550d2a8fe9d406f9dee0534c4a001b2 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T14:51:27Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0550d2a8fe9d406f9dee0534c4a001b22023-10-30T08:50:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12897441289744Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signalingGuido Moll0Guido Moll1Christian Luecht2Michael Adu Gyamfi3Dennyson L. M. da Fonseca4Pinchao Wang5Hongfan Zhao6Zexian Gong7Lei Chen8Muhamad Imtiaz Ashraf9Harald Heidecke10Alexander Maximilian Hackel11Duska Dragun12Klemens Budde13Olaf Penack14Olaf Penack15Gabriela Riemekasten16Otávio Cabral-Marques17Otávio Cabral-Marques18Otávio Cabral-Marques19Otávio Cabral-Marques20Otávio Cabral-Marques21Janusz Witowski22Janusz Witowski23Rusan Catar24Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyBerlin Institute of Healthy (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité Universitätsmedizin Berlin, Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyInterunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of São Paulo (USP), São Paulo, BrazilDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Surgery, Charité Universitätsmedizin Berlin, Berlin, GermanyCellTrend GmbH, Luckenwalde, GermanyDepartment of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyDepartment of Hematology, Oncology and Tumorimmunology, Charité Universitätsmedizin Berlin, Berlin, GermanyBerlin Institute of Health (BIH), Berlin, GermanyDepartment of Rheumatology and Clinical Immunology, University of Lübeck, Lübeck, GermanyInterunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of São Paulo (USP), São Paulo, BrazilDepartment of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, USP, São Paulo, Brazil0Department of Medicine, Division of Molecular Medicine, USP School of Medicine, São Paulo, Brazil1Laboratory of Medical Investigation 29, USP School of Medicine, São Paulo, Brazil2Department of Immunology, Institute of Biomedical Sciences, USP, São Paulo, BrazilDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, Germany3Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, PolandDepartment of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Healthy (BIH), Berlin, GermanyNon-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289744/fullchronic kidney disease (CKD)end-stage renal disease (ESRD)kidney transplantation (KTx)kidney allograft vasculopathyendothelial cells (ECs)non-HLA-directed regulatory autoantibodies (RABs) |
| spellingShingle | Guido Moll Guido Moll Christian Luecht Michael Adu Gyamfi Dennyson L. M. da Fonseca Pinchao Wang Hongfan Zhao Zexian Gong Lei Chen Muhamad Imtiaz Ashraf Harald Heidecke Alexander Maximilian Hackel Duska Dragun Klemens Budde Olaf Penack Olaf Penack Gabriela Riemekasten Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Otávio Cabral-Marques Janusz Witowski Janusz Witowski Rusan Catar Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling Frontiers in Immunology chronic kidney disease (CKD) end-stage renal disease (ESRD) kidney transplantation (KTx) kidney allograft vasculopathy endothelial cells (ECs) non-HLA-directed regulatory autoantibodies (RABs) |
| title | Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling |
| title_full | Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling |
| title_fullStr | Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling |
| title_full_unstemmed | Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling |
| title_short | Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling |
| title_sort | autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via gpcr directed par1 tnf α signaling |
| topic | chronic kidney disease (CKD) end-stage renal disease (ESRD) kidney transplantation (KTx) kidney allograft vasculopathy endothelial cells (ECs) non-HLA-directed regulatory autoantibodies (RABs) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289744/full |
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