TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Alard, Jean-Eric; Gaillard, Fanny; Daridon, Capucine; Shoenfeld, Yehuda; Jamin, Christophe; Youinou, Pierre

doi:10.4049/jimmunol.1000526

Cited by 73 publications

(55 citation statements)

References 57 publications

(61 reference statements)

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“…Moreover, ex vivo studies suggest a role for TLR2 [32][33][34], CD14 [34], GPIbα [35] and TLR8 [36] in aPLA-activated monocytes and EC. Below the role of each receptor/co receptor is described in more detail.…”

Section: Candidate Receptors For Aplamentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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Section: Candidate Receptors For Aplamentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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“…11 Moreover, a role for additional receptors such as TLR2 23,24 and apoER2 21,25,26 in anti-␤ 2 GPImediated EC activation and/or thrombosis has been reported. To address the roles of these receptors in the activation of ECs by anti-␤ 2 GPI Abs, we first transfected cells with siRNA specific for TLR4 or TLR2 or random sequence RNA of identical composition (control); each of the specific siRNAs inhibited the expression of target proteins, whereas the control RNA had no effect.…”

Section: Sirna-mediated Inhibition Of Tlr4 Expression Inhibits Apla/amentioning

confidence: 99%

A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

Allen

Fonseca

Betapudi

et al. 2012

Blood

127

117

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Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly ␤ 2 GPI, and activate endothelial cells (ECs) in a ␤ 2 GPI-dependent manner after binding of ␤ 2 GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-␤ 2 GPI Ab-mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88-dependent pathway leading to activation of NF-B has been proposed. In the present study, we confirm a critical role for TLR4 in anti-␤ 2 GPI Ab-mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-␤ 2 GPI Abs. These results provide new evidence for novel proteinprotein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-␤ 2 GPI-associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome. (Blood. 2012; 119(3):884-893) IntroductionAntiphospholipid syndrome (APS) is characterized by thrombosis and recurrent fetal loss in patients with circulating antiphospholipid Abs (APLAs) and is the most important cause of acquired thrombophilia. [1][2][3] Prospective studies have demonstrated that patients with APS experience significant morbidity and mortality despite recommendations for indefinite anticoagulation. 4 The term "antiphospholipid" is actually a misnomer, because the majority of APLAs are directed against phospholipid-binding proteins, of which ␤ 2 -glycoprotein I (␤ 2 GPI) is the most common. 5,6 The clinical importance of anti-␤ 2 GPI Abs has been demonstrated in several previous reports, 7 and recent studies have shown that affinity-purified human anti-␤ 2 GPI Abs induce thrombosis in mice. 8 Despite the clinical importance of APS, however, its pathogenesis has not been well defined. 1,3,9 One mechanism by which APLAs/anti-␤ 2 GPI Abs may promote thrombosis is through ␤ 2 GPI-dependent activation of endothelial cells (ECs). [10][11][12] ECs play a critical role in the maintenance of blood fluidity through expression of anticoagulant proteins on their luminal surface and the elaboration of antithrombotic substances. 13 However, EC activation leads to loss of these anticoagulant properties and transformation to a pro-adhesive, procoagulant phenotype. 13 APLAs/anti-␤ 2 GPI Abs induce EC activation in vitro and in vivo, as determined by their ability to increase the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1), and tissue factor (TF) and to enhance the expression, synthesis, and/or secretion of pro-inflammatory cytokines and chemokines. 3,[10][11][12] These effects may account for the ab...

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“…Several groups showed that TLR2 but not TLR4 is involved in aPL-mediated cell activation (Satta et al, 2007(Satta et al, , 2011Alard et al, 2010), and a single group report has been published on the direct binding of b2GPI to TLR2 (Alard et al, 2010). By contrast, two groups reported that siRNA-mediated inhibition of TLR2 expression on ECs or anti-TLR2 blocking antibody pretreated monocytes did not affect the aPL-induced pro-coagulation state, suggesting that TLR2 may play a limited role in the activation of unperturbed cells (Lambrianides et al, 2010;Allen et al, 2012).…”

Section: Open Questionsmentioning

confidence: 96%

“…However, in vitro and in vivo experimental models highlight that TLR4 only partially contributes to the thrombogenic effect of aPL, suggesting that more than one receptor may be involved in b2GPI cellular binding. The main candidate receptors for b2GPI on cell membranes have been identified as TLR2, megaline, apolipoprotein Ereceptor2′ (ApoER2′), glycoprotein Iba (GPIba) and platelet factor 4 (PF4) (Kobayashi Review ª 2013John Wiley & Sons Ltd et al, 2001Shi et al, 2006;Alard et al, 2010;Sikara et al, 2010;Romay-Penabad et al, 2011).…”

Section: Open Questionsmentioning

confidence: 99%

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

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SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

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TLR2 Is One of the Endothelial Receptors for β2-Glycoprotein I

Cited by 73 publications

References 57 publications

Receptors involved in cell activation by antiphospholipid antibodies

Receptors involved in cell activation by antiphospholipid antibodies

A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

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