Adipokines and Inflammation Alter the Interaction Between Rheumatoid Arthritis Synovial Fibroblasts and Endothelial Cells

Abstract

Objective: The long-distance migration of rheumatoid arthritis synovial fibroblasts (RASFs) in the severe combined immunodeficiency (SCID) mouse model of rheumatoid arthritis (RA) suggests that an interaction between RASFs and endothelial cells (EC) is critical in this process. Our objective was to assess whether immunomodulatory factors such as adipokines and antirheumatic drugs affect the adhesion of RASFs to ECs or the expression of surface molecules. Methods: Primary ECs or human umbilical vein endothelial cell (HUVEC) and primary RASFs were stimulated with adiponectin (10 µg/mL), visfatin (100 ng/mL), and resistin (20 ng/mL) or treated with methotrexate (1.5 and 1,000 µM) and the glucocorticoids prednisolone (1 µM) and dexamethasone (1 µM), respectively. The expression of adhesion molecules was analyzed by real-time polymerase chain reaction. The interaction of both cell types was analyzed under static (cell-to-cell binding assay) and dynamic conditions (flow-adhesion assay). Results: Under static conditions, adipokines increased mostly binding of RASFs to EC (adiponectin: 40%, visfatin: 28%, tumor necrosis factor α: 49%). Under flow conditions, visfatin increased RASF adhesion to HUVEC (e.g., 0.5 dyn/cm 2 : 75.2%). Reduced adhesion of RASFs to E-selectin was observed after treatment with dexamethasone (e.g., 0.9 dyn/cm 2 : −40%). In ECs, tumor necrosis factor α (TNF-α) increased expression of intercellular adhesion molecule 1 (20-fold) and vascular cell adhesion molecule 1 (77-fold), whereas P-selectin was downregulated after stimulation with TNF-α (−6-fold). Conclusion: The adhesion of RASFs to EC was increased by visfatin under static and flow conditions, whereas glucocorticoids were able to decrease adhesion to E-selectin. The process of migration and adhesion of RASFs to ECs could be enhanced by adipokines via adhesion molecules and seems to be targeted by therapeutic intervention with glucocorticoids.

Adipokines and Autoimmunity in Inflammatory Arthritis

“…Other cell types such as chondrocytes, endothelial cells, and lymphocytes also showed a pro-inflammatory response to adiponectin [ 12 , 24 ], suggesting a mainly pro-inflammatory effect of adiponectin locally within the affected joints ( Figure 1 ). It was shown that adiponectin is able to increase the interaction of RASF with endothelial cells—for example, a cell-to-cell binding assay [ 57 ].…”

“…This is in line with another study using the APO866, an inhibitor blocking the enzymatic Nampt activity, leading to reduced CIA severity and production of inflammatory factors [ 29 ]. Regarding RASF, visfatin was recently shown to increase RASF adhesion to endothelial cells under static as well as flow conditions [ 57 ], potentially promoting angiogenesis and vessel guiding in RA synovial tissue. Visfatin is one of the adipokines with potential as a biomarker but also affecting different cell types in the affected joints in arthritis.…”

Functional disability is related to serum chemerin levels in rheumatoid arthritis

“…Our group has also reported that high levels of E-selectin correlated with tender joint count, morning stiffness, severity of pain, disease activity and high disability index scores in a group of patients with RA 17 . Interestingly, one experimental model described that some adipokines can enhance the interaction between synovial fibroblasts and endothelial cells, whereas glucocorticoids can decrease this process 18 . Therefore, new studies assessing the role of adipokines, cytokines and E-selectin as potential markers of functional disability in patients with RA are still required.…”

Securidaca inappendiculata-Derived Xanthones Protected Joints from Degradation in Male Rats with Collagen-Induced Arthritis by Regulating PPAR-γ Signaling

“…The pathological role of adipokines in RA and many other inflammatory-related diseases have been basically confirmed. 30 Although the mechanism through which adipokines reshape macrophages is not well understood, their impacts on immunity are huge. 31 Aside from the typical adipokines, many macrophages-related cytokines such as MCP-4 and MIP-1 are also defined as adipokines nowadays.…”

“… 31 Aside from the typical adipokines, many macrophages-related cytokines such as MCP-4 and MIP-1 are also defined as adipokines nowadays. 30 , 31 From this perspective, inhibiting the excretion of adipocytes is a feasible strategy to deal with macrophage-controlled inflammations in vivo. In this study, macrophages and pre-adipocytes were located in different chambers in transwell, and the pores between them can only allow adipokines/cytokines and metabolites to permeate.…”