A broad cathepsin inhibitor blocks crystal-stimulated inflammasome-dependent and -independent inflammation and gout arthritis.

BACKGROUND

In the disease gout, monosodium urate (MSU) crystals nucleate in joints and cause acute painful arthritis that can damage the affected joints. Interleukin-1β (IL-1β) released from macrophages plays an essential role in driving this and other crystal-based diseases. Cathepsins participate in particle-induced IL-1β responses.

METHODS

To investigate the potential therapeutic effect of inhibiting cathepsins in these diseases, we used broad spectrum cathepsin inhibitors to block cathepsin catalysis in vitro and in vivo, and measured whether particle-induced inflammasome activation, IL-1β release, peritonitis, and arthritis were suppressed.

RESULTS

Here, we show that in vivo and in vitro, broad-spectrum cathepsin inhibitors, like VBY-825, selectively blocked the activation of NLRP3 inflammasomes in macrophages stimulated with crystals but not with the soluble NLRP3 activator, nigericin. In addition, these inhibitors blocked an inflammasome-independent pathway that also generates mature IL-1β and which contributed substantially to crystal-stimulated inflammation in vivo. Through these effects, the cathepsin inhibitors markedly reduced gout arthritis and inflammation to the unrelated crystal silica (the etiologic agent of silicosis). The cathepsin inhibitors didn't affect any of the inflammatory processes after bioactive IL-1β was present in tissues. They also didn't inhibit LPS-stimulated inflammation in mice or TNFα production from macrophages.

CONCLUSION

These findings provide proof of concept that cathepsin inhibitors are a novel class of anti-inflammatories that can inhibit crystal-stimulated disease with unique mechanisms of action.