Background In a previous study we found that knee joints of mice, susceptible for collagen type II arthritis (DBA/1, B10. RIII) display enhanced sensitivity to immune complexes (ICs) compared to other strains (C57BL/6, BALB/c). Higher and prolonged inflammation and more severe cartilage damage was observed. Murine synovial macrophages as well as IL-1 determine IC mediated arthritis and these cells communicate with ICs using three classes of Fcγ receptors mediating intracellular signalling: FcγRI and III are activating and FcγRII is an inhibitory receptor.
Objectives To investigate whether macrophages of mice that are prone to develop collagen type II arthritis are hypersensitive to ICs by differential FcγR expression and regulation.
Methods Basal expression of FcγR on macrophages of all strains was determined by immunohistochemistry on naïve whole knee joint sections and FACS-analysis using 2.4G2 antibody. Peritoneal macrophages were stimulated with ICs and cells were processed for RT-PCR. Using primers specific for FcγRI, II or III semiquantitative RT-PCR was performed. In addition, peritoneal macrophages of all strains and of mice lacking functional FcγRI and III (FcR γ-chain-/-) were stimulated and tested for the production of IL-1 and stromelysin.
Results Basal expression of FcγR was significantly higher on synovial and peritoneal macrophages of DBA/1 and B10. RIII mice (mean fluorescence resp 440 ± 50 and 360 ± 30) if compared to C57BL/6 and BALB/c (mean fluorescence resp 240 ± 30 and 280 ± 30). After stimulation with ICs, mRNA levels of FcγRI and III were significantly higher in DBA/1 and B10. RIII mice. At day 2, FcγRI expression was 50× higher and FcγRIII was 10× higher. At day 3, FcγRI and III expression were both 10× higher. In contrast, FcγRII mRNA levels were down regulated 50× for DBA/1 and 10× for B10. RIII if compared to C57BL/6 and BALB/c. When DBA/1 and B10RIII peritoneal macrophages were stimulated with ICs (100 μg/ml), a twofold higher and prolonged production of IL-1 was measured if compared to other strains. Macrophages of FcR γ-chain-/- mice showed no detectable amounts of IL-1 after IC stimulation, indicating the role of FcγR in stimulation of cells using ICs. In addition, also stromelysin production was significantly increased in DBA/1 macrophages.
Conclusion Collagen type II arthritis sensitive mice are hyper reactive to IC through higher basal expression of FcγR on macrophages of these strains and stronger up regulation of stimulatory as well as down regulation of inhibitory FcγReceptors, resulting in higher and prolonged expression of IL-1 and stromelysin.
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