Expanded Hemodialysis ameliorates uremia-induced impairment of vasculoprotective KLF2 and concomitant proinflammatory priming of endothelial cells through an ERK/AP1/cFOS-dependent mechanism

Zhao, Hongfan; Wu, Dashan; Gyamfi, Michael Adu; Wang, Pinchao; Luecht, Christian; Pfefferkorn, Anna Maria; Ashraf, Muhammad Imtiaz; Kamhieh-Milz, Julian; Witowski, Janusz; Dragun, Duska; Budde, Klemens; Schindler, Ralf; Zickler, Daniel; Moll, Guido; Catar, Rusan

doi:10.3389/fimmu.2023.1209464

Cited by 3 publications

(2 citation statements)

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“…Human microvascular endothelial cells (HMECs; Catalogue no. CRL-3243) were purchased from ATCC® (Manassas, VA, USA) and used at passages 2-6 and cultured as described previously (19,(38)(39)(40)(41)(42).…”

Section: Culture Of Thp-1 and Hmecs And Flow Cytometry Analysis Of Cd...mentioning

confidence: 99%

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

Moll,

Luecht,

Gyamfi

et al. 2023

Front. Immunol.

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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.

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Section: Culture Of Thp-1 and Hmecs And Flow Cytometry Analysis Of Cd...mentioning

confidence: 99%

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

Moll,

Luecht,

Gyamfi

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Adjunct technology, such as machine perfusion of donor organs (e.g. hypo-vs. normothermic) and kidney/renal replacement therapies (RRTs) comprise another promising new field (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%