The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies

Satta, Nathalie; Dunoyer‐Geindre, Sylvie; Reber, Guido; Fish, Richard J.; Boehlen, Françoise; Kruithof, Egbert K. O.; Moerloose, Philippe de

doi:10.1182/blood-2005-03-024463

Cited by 80 publications

(61 citation statements)

References 51 publications

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“…This observation prompted experiments with fibroblasts deficient in TLR surface expression (33,38). Our results clearly indicated that TLR-4 is required for CCL2 transcription in response to AFA-positive IgG.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that TLRs may also recognize host-derived ligands and contribute to autoimmune inflammatory processes (30). Furthermore, a direct recognition of TLRs by autoantibodies was recently observed in patients with antiphospholipid antibody syndrome and celiac disease (31)(32)(33)(34).…”

mentioning

confidence: 99%

“…Cultured fibroblasts, after undergoing overnight starvation in serum-free medium, were used from passages 3-10. Mouse embryonic fibroblasts (MEFs) deficient in TLR-2 (TLR-2 Ϫ/Ϫ ), TLR-4 (TLR-4 Ϫ/Ϫ ), or TLR-6 (TLR-6 Ϫ/Ϫ ), as well as wild-type MEFs, were a kind gift from Dr. O. Takeuchi (Research Institute for Microbial Disease, Osaka University, Osaka, Japan) (38), made available to us by Dr. P. de Moerloose (Geneva University Hospital) (33). All cell lines were negative for mycoplasma contamination.…”

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confidence: 99%

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Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll‐like receptor 4

Fineschi¹,

Goffin²,

Rezzonico³

et al. 2008

Arthritis & Rheumatism

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Objective. Previous studies have revealed the presence of IgG antifibroblast antibodies (AFAs) capable of binding to the surface of fibroblasts in systemic sclerosis (SSc) sera. Since chemokines may directly or indirectly affect the development of fibrosis, this study was undertaken to investigate the production of chemokines induced by AFAs in fibroblasts, and to characterize the signaling pathways and surface molecules involved.Methods. AFA-positive and AFA-negative IgG were tested on fibroblasts. Chemokine messenger RNA expression was screened by microarray and quantitative reverse transcription-polymerase chain reaction. Production of CCL2, CXCL8, and CXCL10 proteins was assessed by enzyme-linked immunosorbent assay. Pharmacologic inhibitors were used to study signal transduction, with results assessed by Western blotting and immunofluorescence analysis. Fibroblasts with defective expression of Toll-like receptors (TLRs) and anti-TLR monoclonal antibodies (mAb) were used to assess AFA specificity.Results. In human fibroblasts, AFA-positive IgG induced the preferential transcription of chemokines with profibrotic and proangiogenic potential, including, but not exclusively, CCL2, CXCL1, CXCL8, CKLF, and ECGF1, which were distinctly different from those induced by interferon-␥. Levels of CCL2 and CXCL8 proteins were increased in AFA-stimulated fibroblast culture supernatants. AFA binding to fibroblasts resulted in concomitant activation of ERK-1/2, c-Jun, and NF-B. CCL2 production was sensitive to inhibition of both proteasome and JNK, while CXCL8 production was sensitive only to inhibition of proteasome. AFAs failed to up-regulate CCL2 expression in TLR-4-deficient fibroblasts but not in TLR-6-or TLR-2-deficient fibroblasts. Moreover, anti-TLR-4 mAb, but not anti-TLR-2 mAb, partially inhibited the production of CCL2 induced by AFAs in human fibroblasts. Conclusion.Autoantibodies that bind to the surface of fibroblasts may contribute to the pathogenesis of SSc by up-regulating the fibroblast production of profibrotic and proangiogenic chemokines, in a proteasomeand TLR-4-dependent manner.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll‐like receptor 4

Fineschi¹,

Goffin²,

Rezzonico³

et al. 2008

Arthritis & Rheumatism

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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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“…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%

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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The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies

Cited by 80 publications

References 51 publications

Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll‐like receptor 4

Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll‐like receptor 4

Receptors involved in cell activation by antiphospholipid antibodies

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

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