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A novel paradigm for dendritic cells as effectors of cartilage destruction
Lookup NU author(s)
Dr Rachel Lakey
Professor Drew Rowan
Professor John Isaacs
Professor Tim Cawston
Dr Catharien Hilkens
Lakey RL, Morgan TG, Rowan AD, Isaacs JD, Cawston TE, Hilkens CM
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Objective. Dendritic cells (DCs) are enriched in RA synovium and have been implicated in the pathogenesis of RA primarily through their ability to present autoantigen and activate T cells. However, whether DCs play an effector role in cartilage destruction is unknown. The aim of this study was to investigate whether DCs can induce collagen release from cartilage and the mechanism involved. Methods. Human monocyte-derived DCs (mDCs) were activated with CD40 ligand (CD40L) to mimic DC–T-cell interaction, and supernatants were incubated with cartilage explants. Hydroxyproline was assessed as a measure of collagen release and collagenolytic activity was measured by a bioassay using tritiated collagen. TNF- in DC supernatants was measured by specific ELISA. Results. Supernatants from CD40L-activated mDCs, but not unstimulated mDCs, strongly induced the destruction of cartilage collagen. mDC supernatants did not contain collagenases but did induce collagenolytic activity in cartilage explants. Neutralization of TNF- in mDC supernatants completely abolished collagenolysis. Conclusions. This study shows that mDCs, upon CD40-ligation, induce cartilage collagen degradation through an indirect mechanism via the production of TNF-. Our data suggest a potential important role for mDC-derived TNF- in RA, which is in line with the previously reported observations that DCs are a major source of TNF- in early autoimmune lesions and that anti-TNF- therapeutics effectively suppress joint damage in RA patients. We propose that DCs can act as effectors in cartilage destruction, adding a new aspect to the functional role of DCs in RA pathogenesis.
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