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

Abstract

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