Editors' ChoiceInflammation

Casting a NET in Gout

Science Signaling  13 May 2014:
Vol. 7, Issue 325, pp. ec130
DOI: 10.1126/scisignal.2005467

Gout is a painful inflammatory joint disease that is caused by the deposition of monosodium urate (MSU) crystals in joints. In advanced disease, MSU crystals are found in structures called tophi, but whether these are detrimental or beneficial structures is unknown. Schauer et al. found by dual-energy computed tomography that tophi were present during the period of an acute gouty attack and persisted during the symptomatically silent phase of the disease that followed. Tophi in tissue sections from patients contained extracellular DNA and neutrophil elastase, two hallmarks of neutrophil extracellular traps (NETs). Furthermore, there were more cells that had undergone “NETosis” in the synovial fluid from gout patients than that from patients with other forms of arthritis. NETs form at sites of inflammation as neutrophils undergo an oxidative burst, forming net-like structures that trap pathogens and contain enzymes that kill pathogens. In vitro studies with human neutrophils revealed that MSU induced NETosis at low densities of neutrophils and that at higher densities, more typical of those associated with infiltrated tissue, the NETs aggregated. NET aggregation required reactive oxygen species, consistent with the involvement of the neutrophil oxidative burst in this process. Chronic granulomatous disease (CGD) patients have a mutation in an enzyme important for the oxidative burst and exhibit persistent inflammation; mice with a mutation in Ncf1 (Ncf1**) are a model of this disease. After injection of MSU into air pouches, wild-type mice formed more aggregated NETs and Ncf1** mice produced greater amounts of proinflammatory cytokines, a response that was reduced by adoptive transfer of aggregated NETs into the air pouch. The Ncf1** mice also exhibited prolonged paw edema upon injection of MSU into the footpad. In vitro, low-density human neutrophil cultures exposed to MSU had higher concentrations of proinflammatory cytokines and chemokines than did high-density cultures that formed aggregated NETs. Instead, anti-inflammatory mediators were abundant in isolated aggregated NETs. Cytokines or chemokines added to isolated aggregated NETs exhibited a time-dependent decrease in abundance. Proinflammatory mediators were also degraded when added to cell pellets of neutrophils exposed to MSU from healthy patients; this degradation was reduced in pellets from patients with CGD. Proinflammatory mediators were degraded by neutrophil elastase and serine proteases in MSU-induced aggregated NETs. Thus, whereas neutrophils that have undergone NETosis and formed NETs contribute to the inflammatory response, aggregated NETs are involved in resolution of inflammation.

C. Schauer, C. Janko, L. F. Munoz, Y. Zhao, D. Kienhöfer, B. Frey, M. Lill, B. Manger, J. Rech, E. Naschberger, R. Holmdahl, V. Krenn, T. Harrer, I. Jeremic, R. Bilyy, G. Schett, M. Hoffmann, M. Herrmann, Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014). [PubMed]