TLR4 is involved in the pathogenic effects observed in a murine model of antiphospholipid syndrome

• Published in: Clinical immunology (Orlando, Fla.) Vol. 160; no. 2; pp. 198 - 210
• Main Authors: Xie, Hongxiang, Kong, Xiangmin, Zhou, Hong, Xie, Yachao, Sheng, Liangju, Wang, Ting, Xia, Longfei, Yan, Jinchuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015
• Subjects: Allergy and Immunology; Animals; Antibodies, Antiphospholipid - immunology; Antiphospholipid antibodies; Antiphospholipid syndrome; Antiphospholipid Syndrome - immunology; beta 2-Glycoprotein I - immunology; Carotid Artery Thrombosis - chemically induced; Carotid Artery Thrombosis - immunology; Cell Adhesion; Chlorides - toxicity; Disease Models, Animal; E-Selectin - metabolism; Femoral Vein; Ferric Compounds - toxicity; Immunoglobulin G - immunology; Inflammation Mediators - immunology; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-1beta - immunology; Interleukin-6 - immunology; Lipopolysaccharides; Mice; Tissue factor; TLR4; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - immunology; Vascular Cell Adhesion Molecule-1 - metabolism; Venous Thrombosis - chemically induced; Venous Thrombosis - immunology; β2-Glycoprotein I; APS; tissue factor; Toll-like receptor 4; IgG-APS; β2GPI; IgG from patients with antiphospholipid syndrome; ICAM-1; intercellular cell adhesion molecule-1; IL-1β; interleukin-1beta; antiphospholipid antibodies; vascular cell adhesion molecule-1; LPS; IL-6; antiphospholipid syndrome; interleukin 6; TF; VCAM-1; TNF-α; tumor necrosis factor alpha; aPL; β2-glycoprotein I; lipopolysaccharide; TLR4; Tissue factor; Antiphospholipid antibodies; β2-Glycoprotein I; Antiphospholipid syndrome
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2015.05.017

Abstract Antiphospholipid (aPL)/anti-β2-glycoprotein I (β2GPI) antibodies are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing an intracellular signaling and procoagulant/proinflammatory phenotype that leads to thrombosis. There is increasing evidence that Toll-like receptor 4 (TLR4) could serve as an important molecule for anti-β2GPI recognition on target cells. However, few studies have focused on the effects of TLR4 in in vivo models. Here, we investigated the role of TLR4 in the pathogenic effects of aPL/anti-β2GPI more precisely using TLR4-intact (C3H/HeN) and TLR4-defective (C3H/HeJ) mice. C3H/HeN and C3H/HeJ mice were injected with either IgG isolated from patient with APS (IgG-APS) or epitope-specific anti-β2GPI purified from β2GPI peptide-immunized rabbits. We found that, following anti-β2GPI injections and vascular injury, thrombus formation in both the carotid artery and femoral vein was markedly reduced in C3H/HeJ mice when compared with C3H/HeN mice. IgG-APS or anti-β2GPI-induced carotid artery and peritoneal macrophage tissue factor activity/expression was significantly lesser in C3H/HeJ than in C3H/HeN mice. Furthermore, the IgG-APS or anti-β2GPI induced expression of VCAM-1, ICAM-1, and E-selectin in the aorta and of IL-1β, IL-6, and TNF-α in peritoneal macrophages of C3H/HeJ mice was also significantly reduced compared to C3H/HeN mice. Together, these data suggest that TLR4 is involved in the pathogenic effects of aPL/anti-β2GPI antibodies in vivo.