Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Armaka, Marietta UNSPECIFIED UNSPECIFIED UNSPECIFIED Ospelt, Caroline UNSPECIFIED orcid.org/0000-0002-9151-4650 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kollias, George UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; ANTIBODY-INDUCED ARTHRITIS; COLLAGEN-INDUCED ARTHRITIS; INDUCED CELL-DEATH; RHEUMATOID-ARTHRITIS; IKK-BETA; TNF-ALPHA; MICE LACKING; NUCLEAR TRANSLOCATION Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19603