PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity.

Rachel Audo,Catherine Desrumaux,Bernard Combe,Jean-Paul Pais De Barros,Jamila Elhmioui,Michael Hahne,Laurent Lagrost,Claire I Daien,Jacques Morel,Hélène Che,Stéphanie Lemaire,Valérie Deckert

doi:10.1371/journal.pone.0193815

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of joints leading to a progressive and irreversible joints destruction
We demonstrated for the first time that phospholipid transfer protein (PLTP) is overexpressed in synovial tissue of patients with chronic inflammatory rheumatisms, such as RA, when compared to OA
We showed that RA but not OA patients displayed elevated levels of PLTP activity in synovial fluid, which were correlated with pro-inflammatory cytokine (IL1β, IL-6) levels

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of joints leading to a progressive and irreversible joints destruction. The pannus is characterized by neo-vessel formation mediated by angiogenic factors and a synovial hyperplasia, mainly composed of fibroblast-like-synoviocytes (FLS), combined with a massive infiltration of lymphocytes and macrophages. Both increased proliferation and insufficient apoptosis contribute to the local expansion of RA-FLS, which display pseudo-tumoral characteristics and directly participate in inflammation and joints destruction, through production of inflammatory mediators and metalloproteinase (MMP). There is increasing evidence supporting an important link between chronic inflammation and CVD risk, associated with endothelial dysfunction and early atherosclerosis onset [1]. In RA, inflammation is associated with a paradoxical inversion of the usual relationship between CVD risk and lipid levels [2]. There is qualitative change in lipoproteins, as oxidized LDL, small and dense LDL, as well as pro-inflammatory HDL are increased in RA [4, 5]

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