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

Abstract

Objective. To evaluate Fc␥ receptor (Fc␥R) 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 ␣ (TNF␣), interleukin-1␤ (IL-1␤), IL-12, and matrix metalloproteinase 1 (MMP-1). We also sought to determine whether mature macrophages from RA patients express aberrant levels of Fc␥RI, Fc␥RII, and Fc␥RIII, 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. Fc␥R I, II, and III were detected, as well as the proinflammatory mediators IL-1, TNF␣, 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 Fc␥RI, Fc␥RII, and Fc␥RIII 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 Fc␥RII and Fc␥RIII expression in RA synovium than in controls. Fc␥RII and Fc␥RIII, but not Fc␥RI, were highly correlated with the number of synovial macrophages. Consistent with this, TNF␣ expression correlated positively with Fc␥RIII expression. Moreover, MMP-1 expression strongly correlated with Fc␥R I, II, and III expression. Mature macrophages from RA patients showed significantly enhanced expression of Fc␥RII and Fc␥RIII compared with controls. Twentyfour hours after stimulation of RA macrophages with HAGGs, significantly higher production of TNF␣ and gelatinase/collagenase was measured.Conclusion. RA synovium and mature RA macrophages express significantly elevated levels of Fc␥RII and Fc␥RIII, resulting in much higher production of TNF␣ and gelatinase/collagenase after IC stimulation. These data suggest that disturbed expression of Fc␥R on mature synovial macrophages is involved in the pathology of RA.

The Levels of CD16/Fcγ Receptor IIIA on CD14+CD16+Monocytes Are Higher in Children with SeverePlasmodium falciparumAnemia than in Children with Cerebral or Uncomplicated Malaria

“…3). Monocytes with a high level of CD16/Fc␥RIIIA expression may demonstrate more-pronounced effector mechanisms, such as phagocytosis and the production of proinflammatory cytokines (3,36), such as TNF-␣, which has been implicated in the pathogenesis of SMA by decreasing erythropoiesis (8). However, although TNF-␣ levels were elevated at enrollment for all groups, they did not differ between groups (data not shown).…”

“…Increased expression of Fc␥RIIIA could result from the engagement of toll-like receptors by parasite ligands, such as glycosylphosphatidyl inositol and/or parasite DNA/hemozoin complexes (34,42). A number of studies have shown that patients with rheumatoid arthritis, an IC-mediated disease (12,41), overexpress Fc␥RIIIA on peripheral as well as synovial macrophages (3,17). Individuals with the Fc␥RIIIA 158V allele have increased transcription and expression of this receptor on NK cells, but the same has not been reported for macrophages (15).…”

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

“…Patients with RA have an increase in the frequency of CD14 þ CD16 þ monocytes in the synovium and peripheral blood; 44 this was associated with increased TNF-a production following exposure to aggregated IgG. 44,45 DC are known to play an important role in the initiation of the immune response. Abnormalities in DC phenotype and function have been reported in RA.…”

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

“…Immune complexes in joints might thus provide a direct link to cytokine dependent inflammation in RA, via APCs. Coherently, APCs from RA patients have been shown to produce more TNF upon IC triggering than healthy control APCs, which can be explained by increased expression of Fc RII and Fc RIII on these cells [92,93]. High expression of the inhibitory Fc RIIb could play an important role in controlling inflammation by inhibition of activating Fc Rs and TLR4 induced cytokine production in macrophages and DCs [5,94].…”

“…[39,80] ICs in synovial fluid induce TNF release from monocytes. [92,93] TLR8 inhibition prevents "spontaneous" cytokine release by synovial tissue. [87] Interferogenic activity of antitopoisomerase ICs on plasmacytoid DCs.…”