Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation

Shahla Abdollahi-Roodsaz^*, Leo A.B. Joosten^*, Marije I. Koenders^*, Ben T. van den Brand^*, Fons A.J. van de Loo^* and Wim B. van den Berg^*

From the Laboratory of Rheumatology Research and Advanced Therapeutics,^* Department of Rheumatology, the Department of Medicine, and the Nijmegen Institute for Infection, Inflammation and Immunity, (N4i), Radboud University Nijmegen Medical Centre; Nijmegen, The Netherlands

Toll-like receptors (TLRs) may contribute to the pathogenesisof chronic inflammatory destructive diseases through the recognitionof endogenous ligands produced on either inflammation or degenerationof the extracellular matrix. The presence of endogenous TLRagonists has been reported in rheumatoid joints. In the presentstudy, we investigated the significance of TLR2 and TLR4 activationby locally- produced endogenous ligands in the severity of jointinflammation and destruction. Local joint pathology independentof systemic immune activation was induced by overexpressionof interleukin (IL)-1 and TNF in naive joints using adenoviralgene transfer. Here, we report that at certain doses, IL-1-inducedlocal joint inflammation, cartilage proteoglycan depletion,and bone erosion are dependent on TLR4 activation, whereas TLR2activation is not significantly involved. In comparison, tumornecrosis factor ${alpha}$ -driven joint pathology seemed to be less dependenton TLR2 and TLR4. The severity of IL-1-induced bone erosionand irreversible cartilage destruction was markedly reducedin TLR4^–/– mice, even though the degree of inflammationwas similar, suggesting uncoupled processes. Furthermore, theexpression of cathepsin K, a marker for osteoclast activity,induced by IL-1β was dependent on TLR4. Overexpressionof IL-1β in the joint as well as ex vivo IL-1 stimulationof patellae provoked the release of endogenous TLR4 agonistscapable of inducing TLR4-mediated cytokine production. Thesedata emphasize the potential relevance of TLR4 activation inrheumatoid arthritis, particularly with respect to IL-1-mediatedjoint pathology.