Presentation: Different Role of IL-17 and IFNgamma in Fcgamma Receptor Mediated Cartilage Destruction during Immune Complex-mediated Arthritis (2007)

129 Different Role of IL-17 and IFNgamma in Fcgamma Receptor Mediated Cartilage Destruction during Immune Complex-mediated Arthritis

PURPOSE: The activating FcγRI and FcγRIII play a crucial role in mediating severe cartilage destruction during immune complex-mediated arthritis (ICA), which is completely blocked in FcγR knock out mice. Previously it was shown that the Th1 cytokine IFNγ aggravates cartilage destruction via upregulation of activating FcγRs. Recently we found that also the Th17 interleukin-17 (IL-17) aggravates cartilage destruction in immune complex-mediated arthritis models, but the underlying mechanism remains unknown. The objective of the present study is to determine the role of IL-17 in FcγR mediated cartilage destruction during immune complex-mediated arthritis.
METHODS: ICA was passively induced by intra-articular injection of lysozyme-anti-lysozyme complexes. 1·107 pfu AdIL-17 or control vector was injected into the knee joints of naïve mice or one day prior to ICA induction. Total knee joints were isolated 6 days after virus injection to study inflammation and cartilage destruction (proteoglycan depletion, chondrocyte death, MMP-mediated neoepitope expression (VDIPEN), and erosion). Synovium samples were taken for RT-PCR analysis. Macrophage (RAW) and PMN (32Dcl3) cell lines were stimulated with rmIFNγ or rmIL-17 to study FcγR expression using RT-PCR and FACS analysis.
RESULTS: IL-17 overexpression in naïve knee joints resulted in low inflammation and mild cartilage destruction when compared to knee joints injected with control vector. The control vector did not enhance ICA. In marked contrast, IL-17 overexpression prior to ICA induction greatly aggravated ICA mediated PG depletion (290%), chondrocyte death (510%), and VDIPEN expression (283%). This correlated with the severity of joint inflammation. Interestingly, inflammation in the AdIL-17 ICA group was characterised by a sustained, massive influx of PMNs, which was not observed in the control ICA or IFN enhanced ICA group. Strikingly, no differences were found in the IL-17 group with respect to influx of monocytes/ macrophages. RT-PCR analysis of the synovial infiltrate showed that IL-17 overexpression during arthritis clearly enhanced synovial mRNA expression of FcγRI (96 fold), FcγRIIb (114 fold), FcγRIII (87 fold) and FcγRIV (315 fold). In vitro stimulation of macrophages and PMNs with IL-17 showed that, in contrast to IFNγ, IL-17 did not directly upregulate FcγRI, FcγRIII, and FcγRIV.
CONCLUSION: This study shows that IL-17 significantly aggravates cartilage destruction during immune complex-mediated arthritis. In contrast to IFNγ, IL-17 does not upregulate the activating FcγRI, FcγRIII and FcγRIV on macrophages or PMNs. Instead, IL-17 enhances cartilage destruction by strongly elevating the local amount of FcγR bearing neutrophils and underlines an additional mechanism of destruction.

 L.C. Grevers, None; P.L. van Lent, None; M.I. Koenders, None; A.W. Sloetjes, None; W.B. van den Berg, None.