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How neutrophil extracellular traps orchestrate the local immune response in gout

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Abstract

Neutrophil granulocytes possess a large arsenal of pro-inflammatory substances and mechanisms that empower them to drive local acute immune reactions to invading microorganisms or endogenous inflammatory triggers. The use of this armory needs to be tightly controlled to avoid chronic inflammation and collateral tissue damage. In gout, inflammation arises from precipitation of uric acid in the form of needle-shaped monosodium urate crystals. Inflammasome activation by these crystals in local immune cells results in a rapid and dramatic recruitment of neutrophils. This neutrophil influx is accompanied by the infamously intense clinical symptoms of inflammation during an acute gout attack. Neutrophilic inflammation however is equipped with a built-in safeguard; activated neutrophils form neutrophil extracellular traps (NETs). At the very high neutrophil densities that occur at the site of inflammation, NETs build aggregates that densely pack the monosodium urate (MSU) crystals and trap and degrade pro-inflammatory mediators by inherent proteases. Local removal of cytokines and chemokines by aggregated NETs explains how acute inflammation can stop in the consistent presence of the inflammatory trigger. Aggregated NETs resemble early stages of the typical large MSU deposits that constitute the pathognomonic structures of gout, tophi. Although tophi contribute to muscosceletal damage and mortality in patients with chronic gout, they can therefore be considered as a payoff that is necessary to silence the intense inflammatory response during acute gout.

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Acknowledgements

This work was supported by the doctoral training program GRK1660 and the priority program SPP 1468 Osteoimmunology IMMUNOBONE of the German Research Foundation (DFG) and the IMI funded research project BTCure.

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  1. Department of Internal Medicine 3, University of Erlangen-Nuremberg, Glückstraße 4a, 91052, Erlangen, Germany

    Christian Maueröder, Deborah Kienhöfer, Jonas Hahn, Christine Schauer, Bernhard Manger, Georg Schett, Martin Herrmann & Markus H Hoffmann

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  1. Christian Maueröder
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Maueröder, C., Kienhöfer, D., Hahn, J. et al. How neutrophil extracellular traps orchestrate the local immune response in gout. J Mol Med 93, 727–734 (2015). https://doi.org/10.1007/s00109-015-1295-x

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