Background/Purpose:  Gout is one of the most common forms of inflammatory arthritis and is characterized by acute episodes of joint pain. Monosodium urate (MSU) crystals are taken up by macrophages resulting in NLRP3 inflammasome activation and IL-1beta production. The ACR guidelines recommend a daily prophylactic agent, such as colchicine, NSAIDs or corticosteroids, to prevent acute gout flares at the time of initiation of urate-lowering therapy; however, all these agents are associated with possible intolerance or comorbidities.   Chondroitin Sulphate (CS), a natural glycosaminoglycan of the extracellular matrix, has some clinical benefit in symptomatic osteoarthritis but has never been tested in gout.  In vitro, CS has anti-inflammatory effects on chondrocytes and synoviocytes but its effect on macrophages is unknown. The purpose of our study was to evaluate the in vitro effects of CS on MSU-stimulated cytokine production of macrophages.

Methods: THP-1 monocytes were differentiated into mature macrophages using a phorbol ester followed by MSU crystal stimulation in the absence and presence (4 hours prior) of CS in a physiologically achievable range of concentrations (10-200µg/ml). Cell culture media was removed at 24h and analyzed by immunoassay for IL1β. The specificity of inflammasome activation by MSU crystals was tested with a caspase-1 inhibitor (0.01µM-10 µM). Lipopolysaccaride (LPS, 50µg/ml), a toll-like receptor activator, served as a positive control for IL-1 β production.

Results:  MSU crystals ≥10mg/dll consistently increased IL-1β production by macrophages (Figure 1); this effect was inhibitable by the caspase-1 inhibitor confirming inflammasome activation as the source of this cytokine (Figure 2).  Increasing levels of CS resulted in a significant dose-dependent inhibition of MSU stimulated IL-1β production from macrophages (Figure 3).

Conclusion:  Increasing levels of CS attenuate MSU crystal induced macrophage inflammation, suggesting a possible role for CS in gout prophylaxis.

Acknowledgements:  Supported by Bioibérica (Barcelona, Spain), NIH 5T32AI007217-30 (EO) & P01 AR050245