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Nat Commun. 2018 Feb 12;9(1):618. doi: 10.1038/s41467-018-02935-4.

The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts.

Author information

1
Biomedical Sciences Research Center "Alexander Fleming", 16672, Vari, Greece. armaka@fleming.gr.
2
Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich, Wagistrasse 14, Schlieren, 8952, Zurich, Switzerland.
3
Institute for Genetics, University of Cologne, 50674, Cologne, Germany.
4
Biomedical Sciences Research Center "Alexander Fleming", 16672, Vari, Greece. kollias@fleming.gr.
5
Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece. kollias@fleming.gr.

Abstract

NFκB activation and regulated cell death are important in tissue homeostasis, inflammation and pathogenesis. Here we show the role of the p55TNFR-IKK2l-Ripk3 axis in the regulation of synovial fibroblast homeostasis and pathogenesis in TNF-mediated mouse models of arthritis. Mesenchymal-specific p55TNFR triggering is indispensable for arthritis in acute and chronic TNF-dependent models. IKK2 in joint mesenchymal cells is necessary for the development of cartilage destruction and bone erosion; however, in its absence synovitis still develops. IKK2 deletion affects arthritic and antiapoptotic gene expression leading to hypersensitization of synovial fibroblasts to TNF/Ripk1-mediated death via district mechanisms, depending on acute or chronic TNF signals. Moreover, Ripk3 is dispensable for TNF-mediated arthritis, yet it is required for synovitis in mice with mesenchymal-specific IKK2 deletion. These results demonstrate that p55TNFR-IKK2-Ripk3 signalling orchestrates arthritogenic and death responses in synovial fibroblasts, suggesting that therapeutic manipulation of this pathway in arthritis may require combinatorial blockade of both IKK2 and Ripk3 signals.

PMID:
29434332
PMCID:
PMC5809454
DOI:
10.1038/s41467-018-02935-4
[Indexed for MEDLINE]
Free PMC Article

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