title: TLR4 is involved in the pathogenic effects observed in a murine model of antiphospholipid syndrome.
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.
authors.affiliation: Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China. Electronic address: hongzhou@ujs.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Yachao
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Department of Medical Imaging, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Liangju
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
authors.forename: Longfei
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, PR China. Electronic address: yanjinchuan@hotmail.com.
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000276:immunology*; D002448:Cell Adhesion; D002712:Chlorides / Q000633:toxicity; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D005268:Femoral Vein; D005290:Ferric Compounds / Q000633:toxicity; D007074:Immunoglobulin G / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D020246:Venous Thrombosis / Q000139:chemically induced / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology
chemical_list: D017152:Antibodies, Antiphospholipid; D002712:Chlorides; D019040:E-Selectin; D005290:Ferric Compounds; C587672:IL1B protein, mouse; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D053482:beta 2-Glycoprotein I; C440499:lipopolysaccharide, Escherichia coli O111 B4; D018799:Intercellular Adhesion Molecule-1; C024555:ferric chloride
keywords: Antiphospholipid antibodies; Antiphospholipid syndrome; TLR4; Tissue factor; β2-Glycoprotein I