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

Abstract

AbstractIn the disease gout, monosodium urate (MSU) crystals nucleate in joints and cause acute painful arthritis that can damage the affected joints. Similarly, the deposition of other crystals or irritant particles in tissues elicits an inflammatory response that can cause disease. These various particles stimulate macrophages to produce the proinflammatory cytokine interleukin 1β (IL-1β), which is a major driver of the ensuing inflammation. Here we show that in vivo and in vitro, broad spectrum cathepsin inhibitors, like VBY-825, blocked the activation of inflammasomes, which are known to be essential in generating bioactive IL-1β in response to crystals. In addition, the cathepsin 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, which is the etiologic agent in the disease 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 inflammationin mice, or TNF-⍺ production from macrophages. 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.