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Control of early cartilage destruction in inflammatory arthritis by death receptor 3 [Abstract]

Wang, Edward Chung Yern, Newton, Zarabeth, Collins, Fraser, Hayward, Olivia, Perks, William Victor, Singh, Ravinder, Twohig, Jason Peter and Williams, Anwen Sian 2011. Control of early cartilage destruction in inflammatory arthritis by death receptor 3 [Abstract]. Immunology 135 (s1) , p. 153. 10.1111/j.1365-2567.2011.03534.x

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Abstract

Aims: Death Receptor 3 (DR3), the closest tumour necrosis factor receptor superfamily relative to TNFR1, is essential for the accumulation and function of effector T cells in multiple autoimmune and inflammatory disease models, and the development of bone erosions late in animal models of inflammatory arthritis. Here, we investigated the role of DR3 in cartilage destruction during early stages of disease. Methods: DR3-deficient (DR3 KO ) and DR3WT littermates were induced for antigen-induced arthritis (AIA) using methylated BSA. Joints were sectioned and analysed for cartilage destruction using histo- and immunohistochemistry at early (3 days) and late (21 days) timepoints after intra-joint mBSA challenge. MMP-9 ELISAs were performed for in vitro culture experiments. Results: Resistance to cartilage destruction in DR3 KO mice was observed even at early timepoints (17.3% versus 1.9%, DR3WT versus DR3 KO , respectively; P = 0.03), prior to the main accumulation of effector T cells and macrophages into the joint. DR3 KO joints exhibited reduced levels of Ly6G + neutrophils (5.3% versus 1.3%, DR3WT versus DR3 KO , respectively; P = 0.001) and the cartilage-destroying enzyme, matrix metalloproteinase 9 (5.0% versus 2.5%, DR3WT versus DR3 KO , respectively; P = 0.04). In vitro experiments with human cells showed that TL1A, DR3’s only confirmed ligand, did not trigger MMP-9 release, but neutrophils produced >350 times more MMP-9 on a per cell basis than macrophages or fibroblasts (253 500 versus 690 versus 80 pg/h/ 10 6 cells; neutrophils versus macrophages versus RA synovial fibroblasts, respectively). Conclusions: DR3 controls early innate immune-driven development of cartilage destruction in inflammatory arthritis by regulating MMP-9 production and neutrophil accumulation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Publisher: Wiley
ISSN: 1365-2567
Last Modified: 13 Aug 2018 20:32
URI: http://orca.cf.ac.uk/id/eprint/43506

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