Oxidized β2-glycoprotein I induces human dendritic cell maturation and promotes a T helper type 1 response

The human plasma protein β2-glycoprotein I (β2-GPI) is the most common target for antiphospholipid antibodies associated with thrombotic events in chronic disorders related to endothelial cell dysfunction. Crucial information is needed to clarify why this self-abundant protein is targeted by autoimmune responses. In this study, we investigated whether oxidative modification of β2-GPI, either spontaneous in culture wells or induced by treatment with H2O2, renders this self-protein able to activate immature monocyte-derived dendritic cells (DCs) from healthy human donors. Oxidized β2-GPI caused DCs to mature so that CD83 appeared and CD80, CD86, human leukocyte antigen-D region related (HLA-DR), and CD40 increased. The interaction between oxidized β2-GPI and DCs specifically stimulated these cells to secrete interleukin 12 (IL-12), IL-1β, IL-6, IL-8, tumor necrosis factor α (TNF-α), and IL-10. Oxidized β2-GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes, thus inducing T helper 1 (Th1) polarization. The interaction between oxidized β2-GPI and DCs involved interleukin-1 receptor associated kinase (IRAK) phosphorylation and nuclear factor κB (NFκB) activation. Pretreatment of β2-GPI with the antioxidant α-tocopherol prevented DC maturation. These findings show that human oxidized β2-GPI, probably by interacting with a member of the Toll-like receptor (TLR) family, causes DCs to mature. Because this key β2-GPI function requires oxidative modification, in several chronic disorders related to endothelial cell dysfunction oxidative stress might trigger the “autoimmune spiral.”

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Advanced glycation end products of human β2 glycoprotein I modulate the maturation and function of DCs

Blood ◽

10.1182/blood-2010-12-325514 ◽

2011 ◽

Vol 117 (23) ◽

pp. 6152-6161 ◽

Cited By ~ 38

Author(s):

Brigitta Buttari ◽

Elisabetta Profumo ◽

Antonella Capozzi ◽

Francesco Facchiano ◽

Luciano Saso ◽

...

Keyword(s):

Endothelial Cell ◽

Advanced Glycation End Products ◽

Target Antigen ◽

Endothelial Cell Dysfunction ◽

Advanced Glycation ◽

Cell Dysfunction ◽

Glycoprotein I ◽

Glycation End Products ◽

End Products ◽

Chronic Disorders

Abstract In chronic disorders related to endothelial cell dysfunction, plasma β2 glycoprotein I (β2GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why β2GPI triggers autoimmunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified β2GPI is able to interact and activate monocyte-derived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that β2GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-β2GPI. AGE-β2GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-κB. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-β2GPI–stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of β2GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction.

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Impaired Autophagy Induced by oxLDL/β2GPI/anti-β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6662225 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Guiting Zhang ◽

Chao He ◽

Qianqian Wu ◽

Guoying Xu ◽

Ming Kuang ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Signaling Pathways ◽

Western Blotting ◽

Endothelial Injury ◽

Vascular Endothelial ◽

Endothelial Cell Dysfunction ◽

Western Blotting Analysis ◽

Cell Dysfunction ◽

Glycoprotein I

Endothelial cell dysfunction plays a fundamental role in the pathogenesis of atherosclerosis (AS), and endothelial autophagy has protective effects on the development of AS. Our previous study had shown that oxidized low-density lipoprotein/β2-glycoprotein I/anti-β2-glycoprotein I antibody (oxLDL/β2GPI/anti-β2GPI) complex could promote the expressions of inflammatory cytokines and enhance the adhesion of leukocytes to endothelial cells. In the present study, we aimed to assess the effects of oxLDL/β2GPI/anti-β2GPI complex on endothelial autophagy and explore the associated potential mechanisms. Human umbilical vein endothelial cells (HUVECs) and mouse brain endothelial cell line (bEnd.3) were used as models of the vascular endothelial cells. Autophagy was evaluated by examining the expressions of autophagic proteins using western blotting analysis, autophagosome accumulation using transmission electron microscopy, and RFP-GFP-LC3 adenoviral transfection and autophagic flux using lysosome inhibitor chloroquine. The expressions of phospho-PI3K, phospho-AKT, phospho-mTOR, and phospho-eNOS were determined by western blotting analysis. 3-Methyladenine (3-MA) and rapamycin were used to determine the role of autophagy in oxLDL/β2GPI/anti-β2GPI complex-induced endothelial cell dysfunction. We showed that oxLDL/β2GPI/anti-β2GPI complex suppressed the autophagy, evidenced by an increase in p62 protein, a decrease in LC3-II and Beclin1, and a reduction of autophagosome generation in endothelial cells. Moreover, inhibition of autophagy was associated with PI3K/AKT/mTOR and eNOS signaling pathways. Rapamycin attenuated oxLDL/β2GPI/anti-β2GPI complex-induced endothelial inflammation, oxidative stress, and apoptosis, whereas 3-MA alone induced the endothelial injury. Our results suggested that oxLDL/β2GPI/anti-β2GPI complex inhibited endothelial autophagy via PI3K/AKT/mTOR and eNOS signaling pathways and further contributed to endothelial cell dysfunction. Collectively, our findings provided a novel mechanism for vascular endothelial injury in AS patients with an antiphospholipid syndrome (APS) background.

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Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

Journal of Endocrinology ◽

10.1530/joe-16-0340 ◽

2017 ◽

Vol 232 (1) ◽

pp. R27-R44 ◽

Cited By ~ 90

Author(s):

D S Boeldt ◽

I M Bird

Keyword(s):

Endothelial Cell ◽

Endothelial Dysfunction ◽

Cell Function ◽

Endothelial Cell Dysfunction ◽

Hypertensive Disorders Of Pregnancy ◽

Endothelial Cell Function ◽

Vascular Adaptation ◽

Cell Dysfunction ◽

Maternal Adaptation ◽

Flow Through

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell–cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

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