Neutrophil Extracellular Trap–Borne Elastase Prevents Inflammatory Relapse in Intercritical Gout

Abstract

Objective. Gout flares that occur during urate-lowering therapy (ULT) are typically related to the shrinkage of tophi due to aggregated neutrophil extracellular traps (NETs) that have captured monosodium urate crystals in the tissues. The present study was undertaken to analyze the blocking effect of α 1 -antitrypsin on neutrophil elastase, and it was found that α 1 -antitrypsin induced rapid inflammation in the presence of unstable tophi.Methods. Cell-free DNA levels in serum samples were compared between patients who experienced a varying number of gout flares. We investigated whether cell-free DNA in serum samples and α 1 -antitrypsin could be altered after the initiation of ULT. In mice, an injection of monosodium urate monohydrate (MSU) crystals was used to form a mimic of tophi in the peritoneal cavity, which was then analyzed using immunofluorescence staining. Finally, we investigated the relapse of inflammation by analyzing the levels of α 1 -antitrypsin in 2 kinds of artificial tophi and in tophusbearing mice.Results. Levels of cell-free DNA in serum samples correlated with the number of flares experienced by patients with tophaceous gout. ULT induced an increase in cell-free DNA in the serum of patients with tophi. Increases in levels of α 1 -antitrypsin were seen in patients with tophi who received ULT. Chalk-like tophi removed from the peritoneal cavity of mice after MSU crystals induced inflammation showed abundant coexpression of interleukin-1β (IL-1β) and IL-6-associated NETs. A relapse in inflammation was induced by α 1 -antitrypsin during the spontaneous resolution of MSU crystal-induced peritonitis. We observed that α 1 -antitrypsin blocks cytokine degradation by neutrophil elastase during the resolution phase of tophi.Conclusion. ULT causes shrinkage of the tophi reflected by an increase in the levels of cell-free DNA in serum. In the resolution phase of tophi in mice, NET-associated neutrophil elastase degrades proinflammatory cytokines and, thus, ameliorates inflammation.