Armaka, Marietta, Ospelt, Caroline ORCID: 0000-0002-9151-4650, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Kollias, George (2018). The p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts. Nat. Commun., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

NF kappa B 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Armaka, MariettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ospelt, CarolineUNSPECIFIEDorcid.org/0000-0002-9151-4650UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Kollias, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-196031
DOI: 10.1038/s41467-018-02935-4
Journal or Publication Title: Nat. Commun.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; ANTIBODY-INDUCED ARTHRITIS; COLLAGEN-INDUCED ARTHRITIS; INDUCED CELL-DEATH; RHEUMATOID-ARTHRITIS; IKK-BETA; TNF-ALPHA; MICE LACKING; NUCLEAR TRANSLOCATIONMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19603

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