dc.contributor.author
Moll, Guido
dc.contributor.author
Luecht, Christian
dc.contributor.author
Adu Gyamfi, Michael
dc.contributor.author
da Fonseca, Dennyson L. M.
dc.contributor.author
Wang, Pinchao
dc.contributor.author
Zhao, Hongfan
dc.contributor.author
Gong, Zexian
dc.contributor.author
Chen, Lei
dc.contributor.author
Ashraf, Muhamad Imtiaz
dc.contributor.author
Heidecke, Harald
dc.contributor.author
Hackel, Alexander Maximilian
dc.contributor.author
Dragun, Duska
dc.contributor.author
Budde, Klemens
dc.contributor.author
Penack, Olaf
dc.contributor.author
Riemekasten, Gabriela
dc.contributor.author
Cabral-Marques, Otávio
dc.contributor.author
Witowski, Janusz
dc.contributor.author
Catar, Rusan
dc.date.accessioned
2024-07-04T08:28:00Z
dc.date.available
2024-07-04T08:28:00Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/44120
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-43830
dc.description.abstract
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-alpha) 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-alpha 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-alpha 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-alpha gene transcription and TNF-alpha-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.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
chronic kidney disease (CKD)
en
dc.subject
end-stage renal disease (ESRD)
en
dc.subject
kidney transplantation (KTx)
en
dc.subject
kidney allograft vasculopathy
en
dc.subject
endothelial cells (ECs)
en
dc.subject
non-HLA-directed regulatory autoantibodies (RABs)
en
dc.subject
autoantibodies
en
dc.subject
tumor necrosis factor-alpha (TNF-alpha)
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.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
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
1289744
dcterms.bibliographicCitation.doi
10.3389/fimmu.2023.1289744
dcterms.bibliographicCitation.journaltitle
Frontiers in Immunology
dcterms.bibliographicCitation.originalpublishername
Frontiers Media SA
dcterms.bibliographicCitation.volume
14
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
37965310
dcterms.isPartOf.eissn
1664-3224