Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis

Sabrina Pagano; Federico Carbone; Fabienne Burger; Aline Roth; Maria Bertolotto; Bianca Pane; Giovanni Spinella; Domenico Palombo; Aldo Pende; Franco Dallegri; Nathalie Satta; Julien Virzi; Pierre Fontana; François Mach; Fabrizio Montecucco; Nicolas Vuilleumier

doi:10.1160/TH16-03-0229

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(03): 554-564
DOI: 10.1160/TH16-03-0229

Atherosclerosis and Ischaemic Disease

Schattauer GmbH

Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis

Authors

Sabrina Pagano

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

²Department of Human Protein Sciences, Geneva, Switzerland
Federico Carbone

³Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Fabienne Burger

³Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Aline Roth

³Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Maria Bertolotto

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
Bianca Pane

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
Giovanni Spinella

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
Domenico Palombo

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
Aldo Pende

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
Franco Dallegri

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
Nathalie Satta

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

²Department of Human Protein Sciences, Geneva, Switzerland
Julien Virzi

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

²Department of Human Protein Sciences, Geneva, Switzerland
Pierre Fontana

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

²Department of Human Protein Sciences, Geneva, Switzerland

⁶Division of Angiology and Haemostasis, Geneva University Hospitals, Geneva, Switzerland
François Mach

³Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Fabrizio Montecucco

³Division of Cardiology, Geneva University Hospitals, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy
Nicolas Vuilleumier

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

²Department of Human Protein Sciences, Geneva, Switzerland

Abstract

Summary

Humoral autoimmune-mediated inflammation plays a role in atherogenesis, and potentially in arterial thrombosis. Anti-apolipoprotein A-1 (apoA-1) IgG have been reported to represent emergent mediators of atherogenesis through Toll-like receptors (TLR) 2, 4 and CD14 signalling. We investigated the role of anti-apoA-1 IgG on tissue factor (TF) expression and activation, a key coagulation regulator underlying atherothrombosis. Atherothrombosis features were determined by immunohistochemical TF staining of human carotid biopsies derived from patients with severe carotid stenosis undergoing elective surgery (n=176), and on aortic roots of different genetic backgrounds mice (ApoE^-/-; TLR2^-/-ApoE^-/- and TLR4^-/-ApoE^-/-) exposed to passive immunisation with anti-apoA-1 IgG. Human serum levels of anti-apoA-1 IgG were measured by ELISA. In vitro, on human-monocyte-derived-macrophages (HMDM) the anti-apoA-1 IgG increased TF expression and activity were analysed by FACS and chromogenic assays in presence of different pharmacological inhibitors. Human serum anti-apoA-1 IgG levels significantly correlated to intraplaque TF expression in carotid biopsies (r=0.31, p<0.001), which was predictive of clinically symptomatic lesions. On HMDM, anti-apoA-1 IgG induced a TLR2, 4 and CD14-dependent increase in TF expression and activity, involving NF-kappaB and a c-Jun N-terminal kinase-dependent AP-1 transcription factors. In ApoE^-/- mice, anti-apoA-1 IgG passive immunisation significantly enhanced intraplaque TF expression when compared to control IgG. This effect was lost in both TLR2^-/-ApoE^-/- and TLR4^-/-ApoE^-/- mice. These results demonstrate that anti-apoA-1 IgG are associated with TF expression in human atherosclerotic plaques, induce TF expression in vitro and in vivo through TLR2 and 4 signalling, supporting a possible causal relationship between anti-apoA-1 IgG and atherothrombosis.

Keywords

Anti-apoA-1 IgG - tissue factor - atherothrombosis - macrophages - toll-like receptors

Full Text

References

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