Objective: It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)-mediated arthritis depend on Fcgamma receptor type III (FcgammaRIII). Local adenoviral overexpression of interferon-gamma (IFNgamma) in the knee joint prior to onset of IC-mediated arthritis aggravated severe cartilage destruction. In FcgammaRI(-/-) mice, however, chondrocyte death was not enhanced by IFNgamma, whereas matrix metalloproteinase (MMP)-mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcgammaRIII in the latter process. We undertook this study to determine the role of FcgammaRIII in joint inflammation and severe cartilage destruction in IFNgamma-stimulated IC-mediated arthritis, using FcgammaRIII(-/-) mice.
Methods: FcgammaRIII(-/-) and wild-type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNgamma (AdIFNgamma) 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. MMP-mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcgammaR expression levels were determined in synovial washouts and synovium, respectively.
Results: Injection of AdIFNgamma in naive knee joints markedly increased levels of messenger RNA for FcgammaRI, FcgammaRII, and FcgammaRIII. Upon IFNgamma overexpression prior to induction of IC-mediated arthritis, joint inflammation was similar in FcgammaRIII(-/-) 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 1alpha. Furthermore, IFNgamma induced 2-fold and 3-fold increases in chondrocyte death in WT controls and FcgammaRIII(-/-) mice, respectively. Notably, VDIPEN expression also remained high in FcgammaRIII(-/-) mice.
Conclusion: IFNgamma bypasses the dependence on FcgammaRIII in the development of IC-mediated arthritis. Furthermore, both FcgammaRI and FcgammaRIII can mediate MMP-dependent cartilage matrix destruction.