PMC:17821 / 40653-53021 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/17821","sourcedb":"PMC","sourceid":"17821","source_url":"http://www.ncbi.nlm.nih.gov/pmc/17821","text":"Discussion\nWe have found that inflammation and subsequent cartilage destruction caused by immune complexes may be related to the expression of FcγRs on macrophages. Three strains differing in levels of expression of FcγRs were compared. Absence of functional FcγRI and RIII prevents synovial inflammation and cartilage destruction after induction of immune complex arthritis, whereas elevated expression of FcγR on resident joint macrophages of mice susceptible for development of autoimmune arthritis is correlated to markedly more synovial inflammation and cartilage destruction after induction of ICA. The difference in joint inflammation seen within the three strains was not due to genetic differences resulting in a different susceptibility to inflammation, since injection of zymosan or SCWs caused comparable inflammation in the three strains.\nMice lacking the FcR γ-chain were used to investigate the role of FcγRs in ICA. The FcR γ subunit is essential not only for functional FcRI and RIII IgG receptors but also for the high-affinity IgE receptor FcεRI and TcR-CD3 complex of γδT cells. In this passively induced arthritis, B and T cells do not play a role [35]. Even during the chronic phase of ICA as seen in the DBA/1 knee joint, no effect on synovial inflammation was found after giving anti-αβTCR antibodies (data not shown). The high-affinity receptor FcγRI, which binds IgE, is found on mast cells. A previous study showed, however, that experimentally induced ICA in knee joints of mice that are deficient for mast cells (WBB6F1-W/Wv) [42] was not significantly different from that in control mice, indicating that mast cells do not play an important role in ICA.\nThe findings described above suggest that the observed joint inflammation is locally regulated by synovial cells. Earlier studies revealed that macrophage-like type A cells, which form the dominant population (more than 80%) of the lining layer of diarthrodial joints in mice, regulate the onset and chronicity [19,20,21,22] as well as the exacerbation [23] of experimental arthritis. Selective removal of type A cells by clodronate-containing liposomes prior to induction of several experimental arthritides prevented the onset of arthritis and also the larger part of cartilage destruction [21,43]. These studies suggested that synovial macrophages form an important source of chemotactic factors and that activation by immune complexes results in production of chemokines by these cells. It was also found that chronicity of synovial inflammation is mostly seen in models in which immune complexes are present [44]. Immune complexes communicate with macrophages via FcRs, especially the FcγRs, which bind IgG. IgG represents the most dominant immunoglobulin class in the blood and might be involved in activation of macrophages. Coordinate expression of activating FcγRI and RIII and the inhibiting receptor FcγRIIb exposed on joint macrophages probably determines the reaction to immune complexes [15].\nIndeed, we found that the absence of functional FcγRI and RIII completely abrogated the onset of ICA, as was seen in knee joints of FcR γ-chain-/- mice. The proinflammatory cytokine IL-1, which has been shown to regulate synovial inflammation within this model [34,35], was significantly decreased at protein level 24 h after induction. Semiquantitative determination of mRNA levels also suggested downregulation of IL-1. At 6 h after induction of ICA, no difference in cytokine production was found between FcR γ-chain-/- mice and controls. It is therefore possible that the first hours of ICA are mediated by a component other than FcγRs. This component may very well be complement. In addition to IL-1, complement split products have been shown to be important within this model. Depletion of complement generation by cobra venom factor treatment blocked ICA for the most part [35]. In the present study, complement C3c deposition did not differ in knee-joint structures of FcR γ-chain-/- and control mice, suggesting that complement activation does not differ between the two strains; this observation confirms earlier findings [8]. To further investigate whether complement or other mediators play a role in the enhanced inflammation in DBA/1 mice, we compared FcRγ-chain-/- mice in a DBA/1 background with FcR γ-chain+/+ mice. ICA did not develop in FcR γ-chain deficient mice with a DBA/1 background, indicating that in the DBA/1 strain, also, FcRs are crucial mediators. Another difference may be the removal of immune complexes from the joint. Earlier studies revealed that absence of functional FcγRI and RIII retarded the removal of insoluble immune complexes from the body [6]. We found, however, no differences in IgG deposition in the knee joints of the two mouse strains during the first days. The reason for this may be that the arthritogenic molecule we use to elicit ICA has an excellent retention, because of its positive charge. Cationic antigen will be bound electrostatically to the negatively charged structures of the joint [35,39]. Moreover, inflammation in the knee joint may be differently regulated than in other body compartments. The knee-joint cavity is covered mainly with macrophages, which are the first cells that come into contact with the immune complexes during ICA, whereas the kidney and skin contain a broader range of cell types handling immune complexes.\nNext, we investigated ICA in knee joints of DBA/1 mice and found that the severity and the chronicity of arthritis corresponded with a higher level of expression of FcγRs on macrophages. In contrast, ICA in C57BL/6 mice was only mild, without a chronic phase. Macrophages in the knee-joint lining of normal DBA/1 mice stained more intensely than those of normal C57BL/6 mice, suggesting a higher basal level of FcγRII/III expression on DBA/1 mice. Furthermore, higher FcγR expression was not limited to joint macrophages. Peritoneal macrophages showed a twofold higher expression of FcγRs, suggesting that the higher basal expression of FcγRII/III is found on all resident macrophages. Other cell types were also tested for differences in FcγR expression. No significant differences of FcγR expression were found on peripheral blood monocytes nor on a mixed B- and T-cell population, indicating that the differences in expression of FcγRs between C57BL/6 and DBA/1 are not found on all cells of the haematopoietic lineage (unpublished results). Antibodies to FcγRI or FcγRIII are not available and therefore we could not determine the different classes of FcγR separately. Genetic differences in DBA/1 may be responsible for altered FcγR expression, as Holmdahl et aI have pointed out [45]. This would imply that this mouse strain is at higher risk for immune-complex diseases in body compartments that contain macrophages. This is in line with findings in other studies [46]. The finding that FcR γ-chain-/-DBA/1 mice did not show any inflammation when ICA was induced strongly suggests that, in this strain, full-blown ICA is also mediated by FcγRs. Thus the differences in the severity and the chronicity of inflammation during ICA and in the severity of subsequent cartilage damage are likely to be caused by differences in FcγR function or expression. The elevated expression of FcγRs on macrophages was also functional, as was found in experiments in vitro in which IL-1 production was measured after stimulation of macrophages with HAGGs. ICA induction caused much higher levels and longer-lasting production of IL-1 in the knee joints of DBA/1 mice than in the control C57BL/6 mice. IL-1 may well be the factor responsible for the chronicity of the synovial inflammation. Although IL-1 levels at day 3 were found to be below the detection limit of the RIA, blocking of IL-1 with anti-IL-1 antibodies starting at day 3 after ICA induction abrogated the chronic phase completely [34].\nIn addition to inflammation, cartilage destruction was also investigated. In earlier studies, we found that only in those experimental-arthritis models in which immune complexes are present was severe, irreparable cartilage damage found [44]. Mice injected with zymosan or SCW did not suffer irreparable cartilage damage, although a tremendous influx of inflammatory cells in the joint was observed.\nIn FcR γ-chain-/- mice, depletion of PG was entirely absent during ICA. In knee joints of DBA/1 mice, loss of PG from the cartilage matrix was more severe than in C57BL/6 mice. This finding is in line with the respective expression of FcγR on macrophages in these strains and suggests that activation of FcγR may be one of the mechanisms mediating PG loss. Activation of macrophages by FcγRI and RIII leads to the release of IL-1 [47,48], which is the dominant cytokine involved in inhibition of PG synthesis [49,50] and production of aggrecan-degrading enzymes [51,52]. Depletion of PG within this model is probably mediated by aggrecanase [44], an enzyme that recently was identified as a metalloproteinase of the ADAM (A disintegrin and metalloproteinase) family [53]. Aggrecanase neoepitopes were abundantly found during the first phase of this arthritis [44]. Injection of zymosan into the knee joints of the three strains we studied was followed by a comparable depletion of PG; this finding suggests that the three strains have similar potencies to produce aggrecanase.\nSevere cartilage destruction, like chondrocyte death and cartilage erosion, was found only in DBA/1 mice. During the acute phase, PMNs constitute the dominant cell type present in the joint, whereas during the chronic phase, macrophages are the predominant cell type present in the synovium and synovial cavity. FcγR activation on both PMNs and macrophages may lead to the release of oxygen and nitrogen radicals, which in high concentrations can kill chondrocytes either by necrosis or apoptosis [54,55] or may activate latent enzymes in the matrix. Activated macrophages form an important source of latent metalloproteinases such as stromelysin and collagenase; after activation, these enzymes are involved in degradation of the collagen matrix, resulting in severe cartilage destruction [56,57]. Immune complexes activate macrophages in the synovium, causing the release of enzymes that are hindered in their activity by large amounts of inhibitors present in the synovial fluid. Immune complexes present on the cartilage surface may cause PMNs or macrophages to attach to this surface, as we have seen by clear pannus formation on the cartilage during chronic arthritis in the DBA/1 joint. This attachment to the cartilage surface may cause release of enzymes that directly penetrate the cartilage matrix thus escaping from their inhibitors (manuscript in preparation).\nThe present findings partly underline the findings in our previous study, in which an antigen-induced arthritis was produced in FcR γ-/-mice [58], in the sense that stimulation of FcγRs by immune complexes seems necessary in order to induce irreversible cartilage damage. However, in contrast to our present findings, antigen-induced arthritis in FcR γ-chain-/- mice did not significantly reduce joint inflammation. This indicates that within that model, FcRs do not play any role in the chronic phase of inflammation, but are of utmost importance in the induction of severe cartilage damage.\nTo provide conclusive evidence of the role of various classes of FcγR during ICA, experiments are needed in which FcγRs are blocked with specific antibodies, or in which knockout mice are used that lack one of the specific classes of FcγR. However, specific antibodies to FcγRs (2.4G2), once bound to the receptor, have a stimulatory effect and therefore cannot be used in blocking experiments. Experiments using specific knockout mice are therefore now being performed in our laboratory.\nMacrophages are the dominant type of cell present in chronic inflammation during RA and their number has been shown to correlate well with severe cartilage destruction [16,17,18]. Apart from that, in humans, these macrophages express activating Fc receptors, mainly FcγIIIa [26], which may lead to activation of these cells by IgG-containing immune complexes. Fc receptor expression on the surface of these cells may have important implications for joint inflammation and severe cartilage destruction and may form new targets for therapeutic 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