Control of early cartilage destruction in inflammatory arthritis by death receptor 3 [Abstract]
2011
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.
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