Role of Toll‐like Receptors 2 and 4 in Mediating Endothelial Dysfunction and Arterial Remodeling in Primary Arterial Antiphospholipid Syndrome

Abstract

Objective. To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).Methods. Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type (WT) and TLR-knockout mice.Results. APS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium-dependent flow-mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro-oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor ␣ levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR-2 and TLR-4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin-1 receptorassociated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR-2 and TLR-4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxation and increased TF expression in WT mice but not in TLR-2-or TLR-4-knockout mice.Conclusion. This translational study supports the notion that TLR-2 and TLR-4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.

Update on the pathogenesis and treatment of the antiphospholipid syndrome

“…Such hypothesis has been explored in few studies: TLR1, TLR2 and TLR6 have indeed been appointed as candidate b2GPI co-receptors in addition to the ones previously reported [11 && ]. The role of TLR2 and TLR4 has been confirmed in a recent ex-vivo study [12]: an increased mRNA expression of these innate immunity receptors and a markedly raised phosphorylation level of interleukin-1 receptor-associated kinase 1 (IRAK-1) -a major mediator in TLR transduction pathwaywere observed in peripheral blood mononuclear cells (PBMCs) from APS patients. Consistently, TLR1, TLR2 and TLR6 have been shown to co-localize with aPL IgG; in addition, antibodies blocking TLR1, TLR2 and TLR6 decreased aPL-mediated upregulation of tumour necrosis factor (TNF) and tissue factor (TF) in human monocytes [13].…”

Mechanisms of Cellular Activation in the Antiphospholipid Syndrome

“…This suggestion was supported by data from Benhamou et al, showing that deletion of either TLR2 or TLR4 is sufficient to completely abolish the effects of aPL. 72 No in vivo data on the role of TLR2 are currently available so that the role of TLR2 signaling for the APS remains open.…”

Chemerin induced by Treponema pallidum predicted membrane protein Tp0965 mediates the activation of endothelial cell via MAPK signaling pathway

“…Toll‐like receptor 2 (TLR2), an important member of the TLR family, recognizes bacterial lipoproteins and plays a crucial role in the host defense against bacterial infections, including those caused by T. pallidum . Previous studies showed that TLR2 expressed on endothelial cells mediates the initiation of inflammatory signaling cascades . To confirm the roles of TLR2 in the induction of chemerin expression by Tp0965, we transformed HUVECs with shRNA against TLR2 and TLR4, denoting them as HUVECs (shTLR2) and HUVECs (shTLR4), respectively.…”