How complement activation influences the development of chronic synovitis in a mouse model of rheumatoid arthritis

Abstract

Objectives: Chronic synovitis is the main characteristic of rheumatoid arthritis (RA), defined by the proliferation of synovial lining cells, an important source of chemokines and cytokines associated with inflammation. The aim of this study was to examine the influence of complement functional activity on the development of chronic synovitis.Method: The experiments were conducted in zymosan-induced arthritis (ZIA) provoked by intra-articular injection of 180 μg zymosan. Mice were treated with 10 ng/g body weight (bw) cobra venom factor (CVF) on days −3 and −2 or with 10 ng/g bw CVF on days 7, 12, and 17 of ZIA. The percentage of neutrophils (CD11b+Ly6G+), macrophages (F4/80), and complement 5 anaphylatoxin receptor (C5aR)-positive cells in the synovial fluid (SF) were determined by flow cytometry and the expression of C5aR and C3aR in the synovium was detected immunohistochemically.Results: The induction of ZIA in the absence of complement activity strongly inhibited the development of synovitis. By contrast, complement activation during ZIA exacerbated chronic synovitis through an increase in macrophage infiltration, C5aR and C3aR expression in the joints, and C5aR expression on SF cells. Levels of C5a and soluble receptor activator of nuclear factor kappa B ligand (sRANKL) in the SF were elevated whereas neutrophil infiltration and levels of tumour necrosis factor (TNF)-α and interleukin (IL)-6 in the SF were unchanged.Conclusions: Our findings indicate an important role for functional complement activity in the maintenance of chronic synovitis in a model of RA. Antagonizing complement activation represents new possibilities for the amelioration of synovitis symptoms.