TNF\u03b1 expressed on the surface of microparticles modulates endothelial cell fate in rheumatoid arthritis

Cristiana Barbati,Francesca Romana Spinelli,Fabrizio Conti,Marta Vomero,Tania Colasanti,Carlo Perricone,Annacarla Finucci,Francesca Miranda,Simona Truglia,Marco Diociaiuti,Cristiano Alessandri,Guido Valesini,Fulvia Ceccarelli,Lucia Novelli,Sara Ferrigno

doi:10.1186/s13075-018-1768-8

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.

Highlights

Rheumatoid arthritis (RA) is associated with a high prevalence of atherosclerosis
On the basis of this observation, after investigating surface expression of TNFα on MPs purified from patients with RA, we evaluated if MPs were able to modulate endothelial apoptosis and autophagy in vitro, and if TNFα carried on the surface of MPs could be involved in these cellular processes
Our results suggest that MPs isolated from patients with RA could exert their pathological effect on endothelial cells by TNFα expressed on their surface

Summary

Introduction

Rheumatoid 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. Microparticles (MPs) are small membrane vesicles (0.1– 1.0 μm) released by many cell types under physiological and pathological conditions. In the past these particles were considered as inert cell debris, but recently many studies have demonstrated they could be involved in intercellular communication. Due to Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, Barbati et al Arthritis Research & Therapy (2018) 20:273 and autoimmune diseases, such as rheumatoid arthritis (RA) [7]. Previous studies have shown that TNF-inhibitors can improve endothelial function and decrease cardiovascular events in responder patients, highlighting the pro-atherogenic effect of TNFα in RA [9, 10]

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