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A8.10 Cell death sensitisation in TNF-exposed IKK2-deficient synovial fibroblasts regulates disease outcome in modelled arthritis
  1. M Armaka1,
  2. G Kollias1,2
  1. 1Biomedical Sciences Research Center "Alexander Fleming", 16672 Vari, Greece
  2. 2Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece

Abstract

Background and objectives Early investigations into the in-vivo functions of TNF in the huTNF-Tg mice established the pivotal role of this cytokine in the aetiopathogenesis of rheumatoid arthritis. We have previously demonstrated that restricted expression of p55TNFR in synovial fibroblasts (SFs) from huTNF-Tg mice is sufficient to drive the full pathogenic process. Here, we investigated whether expression of p55TNFR on SFs is necessary for the development of arthritis in either the huTNF-Tg or in Collagen-Antibody-Induced-Arthritis (CAIA) models, and how downstream SF- specific signals, such as NFkB, contribute to pathogenesis.

Methods ColVI-Cre mice, providing SF-specific recombination, were crossbred into p55TNFR (p55TNFRSF-KO) or ikk2 conditional knock-out backgrounds (ikk2SF-KO) and/or into hTNF-Tg background. CAIAwas induced by injection of monoclonal antibodies against cartilage antigens, and LPS. The TNF-mediated responses of ikk2-null SFs were examined by RT-PCR, western blot and FACS analysis.

Results SF-specific p55TNFR function is necessary for the development of arthritis in the huTNF-Tg model as well as in CAIA. The huTNF-Tg ikk2SF-KO and ikk2SF-KO mice subjected to CAIA exhibit ameliorated joint pathology indicating that SF ikk2 signals are required for the efficient formation of pannus. Mechanistically, ikk2-ko SFs were extremely susceptible to TNF-induced death while the huTNF-Tg ikk2-ko SFs displayed necroptotic death, suggesting a novel property of chronically TNF-exposed ikk2-deficient SFs in shifting towards necroptosis. Inhibition of necroptosis by the genetic ablation of RIPK3 kinase fully restored the residual synovial inflammation persisting in the huTNF-Tg ikk2SF-KO mice, validating in vivo the physiological role played by necroptosis in chronically TNF-exposed SFs in the absence of NFkB signals.

Conclusions Our results demonstrate a physiologically significant role of the p55TNFR/NFkB pathway in modelled arthritis by identifying the p55TNFR/ikk2/ripk3 axis as regulator of arthritogenic responses downstream of TNF, controlling gene expression and preventing programmed cell death.

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