engleski

7-ketocholesterol-induced pro-inflammatory activation of synovial tissue macrophages in patients with knee osteoarthritis

Introduction: Osteoarthritis (OA) is a chronic joint disease caused by mechanical damage and metabolic factors. Lo w density lipoproteins are proven in synovial fluid. It is known that oxidized lipids from LD L particles, such as 4 - hydroxynonenal (4-HNE) and 7-ketocholesterol (7- KC) act proinflammatory. 7-KC binds for Toll-like receptor (TLR>4 . However, it is not known whether 7-KC can re-programmed synovial tissue macrophages. The aim o f this study was to investigate the expression o f 4-HNE in synovial tissue and to analyze whether 7-KC can drive differentiation o f macrophages toward pro- inflammatory phenotype in respect to lipopolysaccharide (LPS), the prototypic M l polarizing stimuli. Material and Methods: Mature synovial tissue samples were obtained during the knee alloarthroplasty. CD68 was single or double- labelled wit h TLR-4 or 4-HNE in paraffin-embedded tissue sections by immunofluorescence or immunohistology. Synovial tissue mononuclear cells were isolated by enzymatic digestion. The expression o f TLR-4 , arginase-1, iNOS, mannose receptor (MR), decoy D6, CCR5, HLA-DR, CD80, CD86, and FITC- dextran endocytosis were analyzed by flow cytometry in the samples 18-hour cultured with 7- KC, LPS, 7KC+LPS or medium only. Results: Synovial tissue expressed 4-HNE+ and TLR- 4 + cells. Approximatel y 20% o f isolated CD68+ cells express 4-HNE or TLR-4 . 7-KC bound to TLR- 4 on CD68+ cells and decreased the frequency of arginase-1, CCR5 and D6, with the same efficacy as LPS, when compared to the cells cultured in the medium only. 7-KC decreased M R expression marginally and did not affect F1TC dextran (the ligand for MR) endocytosis, as LPS did. Conclusion: Pharmacological dose o f 7-KC binds to TLR- 4 on the surface o f CD68+ synovial cells and supports their M l maturation program. It suggests the role o f oxidized lipids and immunometabolism in the low-grade inflammation during pathogenesis o f OA, as synovial tissue expresses 4-HNE.

osteoarthritis ; 7-ketocholesterol ; macrophages ; synovial tissue

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