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RII Reduces Joint Inflammation and Destruction in Experimental Immune Complex-Mediated Arthritides Not Only by Inhibition of FcRI/III but Also by Efficient Clearance and Endocytosis of Immune Complexes
From the Department of Rheumatology,* University Medical Centre St. Radboud, Nijmegen, The Netherlands; the Department of Human Genetics, UMC, Leiden, The Netherlands; and the Institute of Experimental Dermatology, University of Munster, Germany
Studies of Fc
RII-/- mice identified the inhibitory function of this receptor in joint inflammation and cartilage destruction induced with immune complexes (ICs). To extend our insight in the role of FcRII in arthritis, we explored the role of FcRII in the absence of activating receptors I and III using FcRI/III-/- as well as FcRI/II/III-/- mice. When antigen-induced arthritis (AIA) was elicited, which is a mixture of T cell and IC-driven inflammation, arthritis was almost absent at day 7 in FcRI/III-/- mice. Remarkably, in FcRI/II/III-/- mice, this model induced a tremendously increased arthritis as compared to wild-type controls. This implies that FcRII regulates joint inflammation also in the absence of activating FcRI and III. To confirm the IC specificity of this finding, similar studies were done with ICs or zymosan as arthritogenic stimuli. Strongly elevated inflammation was found in FcRI/II/III-/- mice with IC but not with zymosan. Clearance studies identified accumulation of IgG in the knee joint in the absence of FcRII. Moreover, macrophages expressing only FcRII showed prominent endocytosis of preformed soluble ICs not different from controls. In total absence of FcR (FcRI/II/III-/-), macrophages completely failed to endocytose ICs. Although joint inflammation was much higher in AIA arthritic knee joints of FcRI/II/III-/- and the inflammatory cells still expressed an inflammatory phenotype, severe cartilage destruction (MMP-mediated neoepitopes in the matrix and chondrocyte death) was completely prevented in contrast to the marked destruction which was observed in the wild-type. Our study indicates that FcRII reduces joint inflammation in the absence of activating FcR by promoting endocytosis and clearance of ICs from the joint. Infiltrating cells, which fail to express activating FcR although they still become stimulated are no longer capable of inducing severe cartilage destruction.
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