Joint Inflammation and Chondrocyte Death Become Independent of Fcγ Receptor Type III by Local Overexpression of Interferon-γ During Immune Complex-Mediated Arthritis

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