Pisetsky, David S. Gout, tophi and the wonders of NETs. Arthritis Research & Therapy. 2014; 16:431 doi: 10.1186/s13075-014-0431-2
The neutrophil extracellular traps (NETs) found in gout tophi may hold important clues to the puzzle of immune regulation that could shed light on other diseases, such as lupus, says David S. Pisetsky MD PhD in this editorial.
Why is Pisetsky, whose primary research interest is lupus, editorializing about gout? The two disorders might seem a world apart, he says: Lupus is a chronic antibody-mediated disease, after all, while gout is acute and mediated by cytokines. However, he sees similarities.
Both diseases result from inflammatory responses to single molecules: lupus to DNA, which is built of purine, and gout to uric acid, a byproduct of purine degradation. When released during apoptosis, both molecules trigger inflammation.
So how can the study of gout help lupus? The answer may lie with the NETs found in tophi, which appear to affect immune regulation.
Few researchers have investigated the NET/gout connection. But some recent studies, including one by Schauer and colleagues, are promising.1 This team noted that inflammation was reduced after aggregated NETs broke down cytokines and chemokines.
A NET is a mesh-like structure that forms when chromatin mixes with the contents of neutrophil granules. It can degrade cytokines and chemokines, but how this affects the inflammatory process in gout is unclear. Pisetsky suggests that it could represent a counter-regulatory action that makes the structure inactive.
We can see the effect in the tophus, where we find monosodium urate (MSU), which Pisetsky calls one of the most pro-inflammatory chemicals ever found. The MSU has the potential to cause a tremendous amount of harm, yet it doesn’t, even when a tophus breaks and MSU comes into contact with the surrounding skin.
To examine this effect more closely, Schauer’s research looked at Ncf1++mice, which are deficient in NET actions. These mice developed higher levels of cytokines than wild-type mice when researchers administered MSU crystals into air pouches. When they injected MSU crystals into the foot pads, the NET-deficient mice had a more chronic course of inflammation. Given DNAse treatment to mimic the normal actions of NETs, cytokine production and NET action in the mutant mice declined.
Recent studies “indicate a striking paucity of neutrophils in the tophus," Pisetsky points out. Yet "analysis of proteins in the tophus indicates the presence of myeloperoxidase and histones, both NET constituents.” Perhaps neutrophils remain in the tophus only long enough to set out the NETs, he speculates.
1. Schauer C, Janko C, Munoz LE, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nature Medicine. 2014; Published online 28 April 2014; doi:10.1038/nm.3547