TNFα expressed on the surface of microparticles modulates endothelial cell fate in rheumatoid arthritis

Abstract

BackgroundRheumatoid arthritis (RA) is associated with a high prevalence of atherosclerosis. Recently increased levels of microparticles (MPs) have been reported in patients with RA. MPs could represent a link between autoimmunity and endothelial dysfunction by expressing tumor necrosis factor alpha (TNFα), a key cytokine involved in the pathogenesis of RA, altering endothelial apoptosis and autophagy. The aim of this study was to investigate TNFα expression on MPs and its relationship with endothelial cell fate.MethodsMPs were purified from peripheral blood from 20 healthy controls (HC) and from 20 patients with RA, before (time (T)0) and after (T4) 4-month treatment with etanercept (ETA). Surface expression of TNFα was performed by flow cytometry analysis. EA.hy926 cells, an immortalized endothelial cell line, were treated with RA-MPs purified at T0 and at T4 and also, with RA-MPs in vitro treated with ETA. Apoptosis and autophagy were then evaluated.ResultsRA-MPs purified at T0 expressed TNFα on their surface and this expression significantly decreased at T4. Moreover, at T0 RA-MPs, significantly increased both apoptosis and autophagy levels on endothelial cells, in a dose-dependent manner. RA-MPs did not significantly change these parameters after 4 months of in vivo treatment with ETA.ConclusionsOur data demonstrate that MPs isolated from patients with RA exert a pathological effect on endothelial cells by TNFα expressed on their surface. In vivo and in vitro treatment with ETA modulates this effect, suggesting anti-TNF therapy protects against endothelial damage in patients with RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1768-8) contains supplementary material, which is available to authorized users.

Role of Extracellular Vesicles in Autoimmune Pathogenesis

“…TNF-α is the main cytokine involved in the pathogenesis of RA, which can lead to atherosclerosis and endothelial dysfunction ( 67 , 68 ). It has been demonstrated that MPs in RA patients express TNF-α on their surface ( 69 ), Barbati et al, showed that MPs can induce the activation of asparaginase 3 and TNF-related apoptosis-inducing ligand (TRAIL) and TNF receptor, three independent signals that promote endothelial cell apoptosis, which can lead to the formation of atherosclerosis ( 62 , 70 ). All the above literatures indicate that extracellular vesicles in RA are not only involved in its pathogenesis, but also mainly related to inflammation, atherosclerosis, and impaired endothelial function.…”

Autophagy Modulation in Lymphocytes From COVID-19 Patients: New Therapeutic Target in SARS-COV-2 Infection

“…In addition, we showed that TNF-α carried on microparticles purified from RA patients was able to upregulate autophagy on endothelial cells. In vitro and ex vivo treatment with etanercept blocked this effect (Barbati et al, 2018).…”

Role of Microparticles in the Pathogenesis of Inflammatory Joint Diseases

“…Viñuela-Berni et al observed an increased number of MPs with CD3, CD14, CD19, CD41, and CD63E antigens in plasma of RA patients with high disease activity (DAS 28 > 5.1) [52]. The link between the intensity of inflammation in RA and the number and activity of released microparticles of endothelial origin was confirmed by Barbati et al The total pool of circulating MPs and endothelial MPs (EMPs) initially increased, then decreased after four months of anti-TNFα therapy [58]. The microparticles with CD3, CD14, CD19, CD41, and CD63E antigens also stimulated secretion of TNFα and IL-1, IL-17 by monocytes in vitro [52].…”