NET-borne elastase prevents inflammatory relapse in intercritical gout.

OBJECTIVES: Gout flares accompanied by urate lowering therapy (ULT) are prone to be related to the shrinkage of tophi from aggregated neutrophil extracellular traps (NETs) that had captured monosodium urate crystals in the tissues. In this study, we analysed the blocking effect of α1-antitrypsin on neutrophil elastase, which induced rapid inflammation in the presence of instable tophi.

METHODS: Serum cell-free DNA levels were compared between patients with various numbers of gout flares. We investigated whether serum cell-free DNA and α1-antitrypsin could be altered after ULT. A mimic of tophi formed in the murine peritoneal cavity by injection of MSU crystals was tested by immuno-fluorescence. Finally, we investigated the relapse of inflammation by α1-antitrypsin in two kinds of artificial tophi and in tophus-bearing mice.

RESULTS: Serum cell-free DNA correlated to the numbers of flares in patients with tophaceous gout. ULT induced serum cell-free DNA increase in patients with tophi. An increase of α1-antitrypsin was seen in patients with tophi who received ULT. Chalk-like tophi from the peritoneal cavity of mice after MSU crystals induced inflammation showed abundant co-expression of IL-1β and IL-6 associated NETs. α1-antitrypsin induced the relapse of inflammation during the spontaneous resolution of MSU crystal-induced peritonitis. We observed that α1-antitrypsin blocks the cytokine degradation by neutrophil elastase during the resolution phase of tophi. This article is protected by copyright. All rights reserved.

CONCLUSION: ULT causes shrinkage of the tophi reflected by an increase of the level of serum cell-free DNA. In the resolution phase of murine tophi, the NET-associated neutrophil elastase degrades proinflammatory cytokines and, thus, ameliorates inflammation.