Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling

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art_MOLL_Autoantibodies_from_patients_with_kidney_allograft_vasculopathy_stimulate_2023.PDF (4.08 MB)
Citações na Scopus
2
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
FRONTIERS MEDIA SA
Autores
MOLL, Guido
LUECHT, Christian
GYAMFI, Michael Adu
FONSECA, Dennyson L. M. da
WANG, Pinchao
ZHAO, Hongfan
GONG, Zexian
CHEN, Lei
ASHRAF, Muhamad Imtiaz
HEIDECKE, Harald
Citação
FRONTIERS IN IMMUNOLOGY, v.14, article ID 1289744, 15p, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
Palavras-chave
chronic kidney disease (CKD), end-stage renal disease (ESRD), kidney transplantation (KTx), kidney allograft vasculopathy, endothelial cells (ECs), non-HLA-directed regulatory autoantibodies (RABs), autoantibodies, tumor necrosis factor-alpha (TNF-alpha)
URI
https://observatorio.fm.usp.br/handle/OPI/57334
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - LIM/29
Artigos e Materiais de Revistas Científicas - ODS/03