Synovial tissue macrophage populations and articular damage in rheumatoid arthritis

Objective. Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/ chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA.Methods. Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680.Results. The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation.Conclusion. Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis.

Section: Discussionmentioning

confidence: 99%

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Galligan¹,

Fish²

2012

“…Since the percentage of macrophages is related to the severity of cartilage destruction (3,4), and no difference in inflammatory mass was present between WT control and Fc␥RIII ؊/؊ mice when IFN␥ was overexpressed, comparison of cartilage damage between these groups was simplified. MMPs mediate severe cartilage destruction found in IC-mediated arthritis.…”

Section: Discussionmentioning

confidence: 99%

Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

Nabbe¹,

Boross²,

Holthuysen³

et al. 2005

Objective. It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)-mediated arthritis depend on Fc␥ receptor type III (Fc␥RIII). Local adenoviral overexpression of interferon-␥ (IFN␥) in the knee joint prior to onset of IC-mediated arthritis aggravated severe cartilage destruction. In Fc␥RI Ϫ/Ϫ mice, however, chondrocyte death was not enhanced by IFN␥, whereas matrix metalloproteinase (MMP)-mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating Fc␥RIII in the latter process. We undertook this study to determine the role of Fc␥RIII in joint inflammation and severe cartilage destruction in IFN␥-stimulated IC-mediated arthritis, using Fc␥RIII ؊/؊ mice.Methods. Fc␥RIII ؊/؊ and wild-type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFN␥ (AdIFN␥) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC-mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMPmediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and Fc␥R expression levels were determined in synovial washouts and synovium, respectively.Results. Injection of AdIFN␥ in naive knee joints markedly increased levels of messenger RNA for Fc␥RI, Fc␥RII, and Fc␥RIII. Upon IFN␥ overexpression prior to induction of IC-mediated arthritis, joint inflammation was similar in Fc␥RIII ؊/؊ and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1␣. Furthermore, IFN␥ induced 2-fold and 3-fold increases in chondrocyte death in WT controls and Fc␥RIII ؊/؊ mice, respectively. Notably, VDIPEN expression also remained high in Fc␥RIII ؊/؊ mice.Conclusion. IFN␥ bypasses the dependence on Fc␥RIII in the development of IC-mediated arthritis. Furthermore, both Fc␥RI and Fc␥RIII can mediate MMP-dependent cartilage matrix destruction.

“…Macrophages are thought to play a crucial role in the perpetuation of inflammation and in the development of irreversible cartilage damage during RA (5)(6)(7). In the present study, we have clearly demonstrated that RA macrophages matured in vitro show higher expression of Fc␥RII compared with macrophages from healthy controls.…”

Section: Discussionmentioning

confidence: 99%

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

Blom¹,

Radstake²,

Holthuysen³

et al. 2003

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.