Increased expression of Fcγ receptors II and III on macrophages of rheumatoid arthritis patients results in higher production of tumor necrosis factor α and matrix metalloproteinase

Objective

To evaluate Fcγ receptor (FcγR) expression on synovial macrophages from rheumatoid arthritis (RA) patients and to determine whether this expression correlates with the production of the proinflammatory cytokines tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β), IL‐12, and matrix metalloproteinase 1 (MMP‐1). We also sought to determine whether mature macrophages from RA patients express aberrant levels of FcγRI, FcγRII, and FcγRIII, and to determine the production of inflammatory mediators after immune complex (IC) stimulation.

Methods

Immunohistochemistry was performed on cryostat sections of synovial biopsy specimens obtained from 27 RA patients and 5 controls. FcγR I, II, and III were detected, as well as the proinflammatory mediators IL‐1, TNFα, IL‐12, and MMP‐1. Monocytes were isolated from the blood of 10 RA patients and 10 healthy controls and cultured for 7 days with macrophage colony‐stimulating factor to obtain macrophages. Using fluorescence‐activated cell sorting, the expression of FcγRI, FcγRII, and FcγRIII was determined. On day 7, macrophages were stimulated with heat‐aggregated gamma globulins (HAGGs) for 24 hours. Production of cytokines was measured using enzyme‐linked immunosorbent assay, and production of gelatinases/collagenases was measured by degradation of fluorescent gelatin.

Results

Immunohistochemistry showed higher FcγRII and FcγRIII expression in RA synovium than in controls. FcγRII and FcγRIII, but not FcγRI, were highly correlated with the number of synovial macrophages. Consistent with this, TNFα expression correlated positively with FcγRIII expression. Moreover, MMP‐1 expression strongly correlated with FcγR I, II, and III expression. Mature macrophages from RA patients showed significantly enhanced expression of FcγRII and FcγRIII compared with controls. Twenty‐four hours after stimulation of RA macrophages with HAGGs, significantly higher production of TNFα and gelatinase/collagenase was measured.

Conclusion

RA synovium and mature RA macrophages express significantly elevated levels of FcγRII and FcγRIII, resulting in much higher production of TNFα and gelatinase/collagenase after IC stimulation. These data suggest that disturbed expression of FcγR on mature synovial macrophages is involved in the pathology of RA.