- CD4+CXCR3+ T cells and plasmacytoid dendritic cells enhanced atherosclerosis in patients with Systemic Lupus Erythematosus (SLE)
SACRE K1,2,3, Clément M4, Charles N2,3, Escoubet B5, Guedj K4, Chauveheid MP1, Ollivier V4, Caligiuri G3,4, Nicoletti A3,4; Papo T1,2,3
1-Service de Médecine Interne, Hôpital Bichat, Université Paris Diderot, PRES Sorbonne Paris Cité, Assistance Publique Hôpitaux de Paris, Paris, France
2-INSERM U1149, Université Paris Diderot, Laboratoire d’excellence INFLAMEX, PRES Sorbonne Paris Cité, Paris, France
3-Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation and Remodelling in Renal and Respiratory Diseases), Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
4-INSERM U1148, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France
5-Département de Physiologie, Hôpital Bichat, Université Paris Diderot, PRES Sorbonne Paris Cité, Assistance Publique Hôpitaux de Paris, Paris, France
Introduction Cardiovascular disease (CVD) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). As atherosclerosis is itself immune-mediated, specific features of SLE-associated immunity might explain accelerated cardiovascular disease in this population. We herein investigated the role of T cells and plasmacytoid dendritic cells (pDCs) – both crucial in SLE pathogenesis – in atherosclerosis associated with SLE.
Results We first observed that peripheral CD4+T cells expressing CXCR3, a chemokine receptor involved in recruitment of T cells in atherosclerotic lesions, were high in SLE patients and correlated with atherosclerosis, as assessed by measurements of carotid internal carotid artery wall thickness (ICWT). Such CD4+CXCR3+ T cells were antigen-primed and produced high levels of TNF-α. On the other hand, CXCR3 ligands (i.e. CXCL9, CXCL10, CXCL11) were high is SLE patients with active disease. In addition, IFN-α produced by pDCs upon TLR-9 stimulation induced both the in vitro expansion of CD4+CXCR3+ T cells and production of CXCR3 ligands by human coronary endothelial cells (HCEC). Eventually, TLR-9 stimulation 1-induced the development of anti-ssDNA autoantibodies and a significant rising of CXCL10 in serum, 2-enhanced CD4+CXCR3+ T cells recruitment in arterial wall, and 3-promoted atheroslerosis in apoE-/- mice.
Conclusion SLE-associated atherosclerosis may be driven by a positive pathway in which IFN-α produced by pDCS promotes the expansion of a high frequency of antigen-stimulated, CD4+CXCR3+ T cells and induces endothelial cells to secrete CXCR3 ligands, which itself drive progressive infiltration of the arterial wall and atherosclerosis.