Lipid presentation by the protein C receptor links coagulation with autoimmunity

Science ◽  
2021 ◽  
Vol 371 (6534) ◽  
pp. eabc0956 ◽  
Author(s):  
Nadine Müller-Calleja ◽  
Anne Hollerbach ◽  
Jennifer Royce ◽  
Svenja Ritter ◽  
Denise Pedrosa ◽  
...  
Keyword(s):  
Cell Surface ◽  
Lupus Erythematosus ◽  
Protein C ◽  
Innate Immune ◽  
Surface Lipid ◽  
Endothelial Protein C Receptor ◽  
Autoantibody Production ◽  
Protein Receptor ◽  
Lysobisphosphatidic Acid ◽  
Lipid Presentation

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7–dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid–protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.

Effects of oral anticoagulant therapy and haplotype 1 of the endothelial protein C receptor gene on activated protein C levels

2012 ◽  
Vol 107 (03) ◽  
pp. 448-457 ◽  
Author(s):  
Pilar Medina ◽  
Elena Bonet ◽  
Silvia Navarro ◽  
Laura Martos ◽  
Amparo Estellés ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Lupus Erythematosus ◽  
Protein C ◽  
Oral Anticoagulant Therapy ◽  
Receptor Gene ◽  
Oral Anticoagulants ◽  
Activated Protein C ◽  
Endothelial Protein C Receptor ◽  
Haplotype 1

SummaryOral anticoagulants (OACs) reduce activated protein C (APC) plasma levels less than those of protein C (PC) in lupus erythematosus and cardiac patients. Carriers of the H1 haplotype of the endothelial PC receptor gene (PROCR) have higher APC levels than non-carriers. We aimed to confirm these results in a large group of patients treated with OACs because of venous thromboembolism (VTE) and to assess whether the effect is influenced by the PROCR H1 haplotype. We evaluated APC, PC, and factor (F)II levels in 502 VTE patients (158 with and 344 without OACs) and in 322 healthy individuals. Mean APC, PC and FII levels were significantly lower in OAC patients than in patients not taking OACs. During anticoagulant therapy, the FII/PC ratios were independent of the PC values, whereas APC/FII and APC/PC ratios significantly increased when FII and PC levels decreased. Of the 22 OAC patients carrying the H1H1genotype, 11 (50%) showed APC/PCag ≥2.0 and 10 (45%) APC/ FIIag ratios ≥2.0, whereas for the 49 OAC patients non-carrying the H1 haplotype these figures were 6 (12%) and 4 (8%), respectively (p<0.001). Barium citrate adsorption of plasma from OAC patients showed that most of the circulating free and complexed APC, but only part of PCag, is fully carboxylated. In conclusion, during anticoagulant therapy VT patients have APC levels disproportionately higher than the corresponding PC levels, mainly due to the presence of the PROCR H1 haplotype. Furthermore, a sufficiently carboxylated PC Gla-domain seems to be essential for PC activation in vivo.

A Novel Mechanism of Endothelial Protein C Receptor Release, in Microparticulate Form, by Activated Protein C.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1923-1923
Author(s):  
Margarita Perez-Casal ◽  
Kenji Fukudome ◽  
Cheng Hock Toh
Keyword(s):  
Cell Surface ◽  
Protein C ◽  
Umbilical Vein ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Endothelial Protein C Receptor ◽  
Factor Va ◽  
Metalloproteinase Inhibitors ◽  
Cytokine Stimulation ◽  
Umbilical Vein Endothelial Cells

Abstract Activated protein C (APC) administration is now used for treating patients with severe sepsis. We investigated its effect on primary, physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor (EPCR) release from the cell surface. Exposure of human umbilical vein endothelial cells or monocytes to APC (from physiological levels of 0.5 up to 100nM) resulted in the increasing release of EPCR-containing microparticles (EPCR-MP), as demonstrated by confocal microscopy. Further characterisation through flow cytometry showed a concomitant fall in EPCR levels from the cell surface. This release of EPCR could not be inhibited by the metalloproteinase inhibitors 1, 10-phenanthroline or Ro31-9790, unlike soluble EPCR (sEPCR) that is metalloproteinase cleaved at the cell surface following thrombin or pro- inflammatory cytokine stimulation. Western blotting confirmed the molecular weight of EPCR-MP to be identical to the full-length membrane form (49 kD) and different from sEPCR (45 kDa). APC was also bound to EPCR-MP and could be quantified by ELISA using EPCR capture and APC detection by chromogenic substrate, S2366. Using an initial factor Va incubation step followed by a prothrombinase assay, the APC bound to EPCR-MP could significantly reduce thrombin generation. This was abrogated in the presence of excess α1-antitrypsin, an APC inhibitor. By contrast, APC bound to sEPCR could no longer inactivate factor Va. Further characterisation showed the APC induction of EPCR-MP to be time dependent with increasing release over 24 hours, as quantified by ELISA. The phenomenon also required the active site of APC. Neither protein C, heat-inactivated or D-Phe-Pro-Arg-chloromethylketone-blocked APC could induce EPCR-MP formation. Co-incubation with hirudin (6mM) did not alter the APC effect and excluded any role of contaminating thrombin. This novel observation provides new insights into the consequences of APC therapy in the septic patient as well as demonstrating for the first time that there can be 2 circulating forms of EPCR. Unlike sEPCR however, EPCR-MP can facilitate and potentially disseminate the anticoagulant activity of bound APC.

scholarly journals Evaluation of endothelial protein C receptor in patients with systemic lupus erythematosus: correlation with disease activity and lupus nephritis

2015 ◽  
Vol 42 (2) ◽  
pp. 68
Author(s):  
Asmaa Shaaban ◽  
NadiaAbd El-Salam Elkadery ◽  
HebatallahAhmed El-Shamy ◽  
RanaAhmed El-Hilaly ◽  
NesrineAly Mohamed ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Protein C ◽  
Endothelial Protein C Receptor ◽  
Systemic Lupus

scholarly journals Endothelial Protein C Receptor (EPCR), Protease Activated Receptor-1 (PAR-1) and Their Interplay in Cancer Growth and Metastatic Dissemination

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 51 ◽  
Author(s):  
Marek Z. Wojtukiewicz ◽  
Dominika Hempel ◽  
Ewa Sierko ◽  
Stephanie C. Tucker ◽  
Kenneth V. Honn
Keyword(s):  
Cell Surface ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Protein C ◽  
Critical Role ◽  
Activated Protein C ◽  
Cancer Growth ◽  
Endothelial Protein C Receptor ◽  
Surface Receptors ◽  
Protease Activated Receptor 1

Endothelial protein C receptor (EPCR) and protease activated receptor 1 (PAR-1) by themselves play important role in cancer growth and dissemination. Moreover, interactions between the two receptors are essential for tumor progression. EPCR is a cell surface transmembrane glycoprotein localized predominantly on endothelial cells (ECs). It is a vital component of the activated protein C (APC)—mediated anticoagulant and cytoprotective signaling cascade. PAR-1, which belongs to a family of G protein–coupled cell surface receptors, is also widely distributed on endothelial and blood cells, where it plays a critical role in hemostasis. Both EPCR and PAR-1, generally considered coagulation-related receptors, are implicated in carcinogenesis and dissemination of diverse tumor types, and their expression correlates with clinical outcome of cancer patients. Existing data explain some mechanisms by which EPCR/PAR-1 affects cancer growth and metastasis; however, the exact molecular basis of cancer invasion associated with the signaling is still obscure. Here, we discuss the role of EPCR and PAR-1 reciprocal interactions in cancer progression as well as potential therapeutic options targeted specifically to interact with EPCR/PAR-1-induced signaling in cancer patients.

scholarly journals Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Carlos Wong-Baeza ◽  
Alonso Tescucano ◽  
Horacio Astudillo ◽  
Albany Reséndiz ◽  
Carla Landa ◽  
...  
Keyword(s):  
B Cells ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Autoantibody Production ◽  
Immune System Activation ◽  
Expression Of Genes ◽  
Nuclear Antigens ◽  
Proinflammatory Gene ◽  
Toll Like Receptor 2

Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.

scholarly journals Soluble and membranous endothelial protein C receptor in systemic lupus erythematosus patients: Relation to nephritis

2019 ◽  
Vol 41 (1) ◽  
pp. 25-30 ◽  
Author(s):  
Asmaa A. Shaaban ◽  
Nadia A. Elkadery ◽  
Hebatallah A. El-Shamy ◽  
Rana A. El-Hilaly ◽  
Nadia G. El-Hefnawy ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Protein C ◽  
Endothelial Protein C Receptor ◽  
Systemic Lupus

scholarly journals Systemic Exposure to Irradiated Apoptotic Cells Induces Autoantibody Production

1998 ◽  
Vol 188 (2) ◽  
pp. 387-392 ◽  
Author(s):  
Dror Mevorach ◽  
Jun Liang Zhou ◽  
Xin Song ◽  
Keith B. Elkon
Keyword(s):  
Immune Response ◽  
Cell Surface ◽  
Lupus Erythematosus ◽  
Apoptotic Cell ◽  
Systemic Exposure ◽  
Intravenous Route ◽  
Apoptotic Cells ◽  
Autoantibody Production ◽  
Cell Clearance ◽  
Antinuclear Autoantibodies

During apoptotic cell death, cell surface ligands initiate phagocytosis of the dying cell. Clearance of these apoptotic cells is thought to occur without an immune response. Since a number of autoantigens are located at the cell surface or within apoptotic blebs, we examined whether exposure of mice to syngeneic apoptotic cells by the intravenous route could induce autoantibody production. Normal mice injected with syngeneic apoptotic thymocytes developed antinuclear autoantibodies and anticardiolipin and anti-ssDNA antibodies. The autoantibody levels were generally lower than those observed in MRL/Faslpr mice and were transient. Surprisingly, six out of six immunized mice demonstrated immunoglobulin G deposition in the glomeruli several months after immunization. These findings indicate that systemic exposure to apoptotic cells can induce an immune response in normal mice, and may help to explain antigen selection and initiation of the immune response in diseases characterized by increased rates of apoptosis such as AIDS and, possibly, systemic lupus erythematosus.

Sign in / Sign up

Export Citation Format

Share Document