Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Toll-Like Receptor 2 Negatively Regulates FCg Receptor Response in Macrophages and Inhibits FCgR-Mediated Arthritis.
Abdollahi-Roodsaz3, Shahla, Koenders2, Marije I., van de Loo4, Fons A. J., Van Den Berg1, Wim B.
Radboud Univ Nijmegen Med Cntr, Nijmegen, The Netherlands
Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen
Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, Nijmegen, The Netherlands
Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Current evidence indicates that Toll-like receptors (TLRs) and FCg receptors (FCgRs) are involved in the pathogenesis of arthritis and mutual regulatory functions for these innate immune receptors have been suggested as well. In the present study, we investigated the involvement of TLR2 in regulation of FCgR response and assessed the functional consequences for the development of arthritis.
Peritoneal macrophages from naïve wild-type (WT) and TLR2-/- mice were stimulated with heat-aggregated gamma globulins (HAGGs) and immune complexes, and cytokine production was evaluated. Although no clear shift was noticed in the expression pattern of activating and inhibitory FCgRs, macrophages from TLR2-/- mice showed a greatly exaggerated functional response (>6 fold) and produced much more TNFa, IL-1b and IL-6 upon FCgR triggering compared to WT cells.
To assess the functional consequence of enhanced FCgR response in TLR2-/- condition for arthritis, FCgR-driven serum-transfer arthritis was induced by i.p. injection of serum from arthritic K/BxN mice. TLR2-/- mice showed an accelerated onset of arthritis and had a strikingly enhanced disease severity. Marked increase in inflammation was also obvious in the knee joints in addition to the paws. Furthermore, gene expression of several proinflammatory cytokines, including TNF, IL-1 and IL-6, and certain matrix metalloproteinases was enhanced in synovial tissue of TLR2-/- mice compared to WT.
PCR analysis revealed that basal expression of activating and inhibitory FCgRs in peritoneal macrophages, spleen and synovial tissue of arthritic mice was not affected by TLR2 deficiency. Furthermore, regulation of FCgR expression in macrophages upon stimulation with K/BxN serum and HAGGs was not affected. However, macrophages from arthritic TLR2-/- mice released significantly more TNF and IL-6 upon general PMA/ionomycin stimulation, while having similar levels of IL-10 compared to WT cells. This indicates a potentiated M1 and similar M2 profile in macrophages from arthritic mice in the absence of TLR2. Importantly, FCgR triggering of macrophages isolated briefly after disease induction and before appearance of clinical differences using immune complexes resulted in markedly higher levels of TNF and IL-6, but not IL-10, in TLR2-/- condition. Unaltered response of TLR2-/- macrophages to IL-1 as control excluded a non-specific effect.
These findings indicate an important regulatory function of TLR2 in macrophage FCgR response with remarkable consequences for arthritis expression. A protective role of TLR2 in immune-complex driven arthritis beyond its previously-described role in promoting regulatory T cell function may provide a relevant therapeutic intervention for the future treatment of RA.
To cite this abstract, please use the following information:
Abdollahi-Roodsaz, Shahla, Koenders, Marije I., van de Loo, Fons A. J., Van Den Berg, Wim B.; Toll-Like Receptor 2 Negatively Regulates FCg Receptor Response in Macrophages and Inhibits FCgR-Mediated Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2230