NET Formation Drives Tophaceous Gout

Wang Y, Han J, Knopf J, Zhu L, Zhao Y, Liu L, Herrmann M (2025)

Publication Type: Journal article, Review article

Publication year: 2025

Journal

Gout, Urate, and Crystal Deposition Disease MDPI

Book Volume: 3

Article Number: 16

Journal Issue: 3

DOI: 10.3390/gucdd3030016

Abstract

Gout is a chronic inflammatory disease characterized by the deposition of monosodium urate (MSU) crystals within joints, leading to recurrent acute flares and long-term tissue damage. While various hypotheses have been proposed to explain the self-limiting nature of acute gout attacks, we posit that aggregated neutrophil extracellular traps (aggNETs) play a central role in this process. This review focuses on the mechanisms underlying MSU crystal-induced formation of neutrophil extracellular traps (NETs) and explores their dual role in the clinical progression of gout. During the initial phase of acute flares, massive NET formation is accompanied by the release of preformed inflammatory mediators, which is a condition that amplifies inflammatory cascades. As neutrophil recruitment reaches a critical threshold, the NETs tend to form high-order aggregates (aggNETs). The latter encapsulate MSU crystals and further pro-inflammatory mediators within their three-dimensional scaffold. High concentrations of neutrophil serine proteases (NSPs) within the aggNETs facilitate the degradation of soluble inflammatory mediators and eventually promote the resolution of inflammation in a kind of negative inflammatory feedback loop. In advanced stages of gout, MSU crystal deposits are often visible via dual-energy computed tomography (DECT), and the formation of palpable tophi is frequently observed. Based on the mechanisms of resolution of inflammation and the clinical course of the disease, building on the traditional static model of “central crystal–peripheral fibrous encapsulation,” we have expanded the NETs component and refined the overall concept, proposing a more dynamic, multilayered, multicentric, and heterogeneous model of tophus maturation. Notably, in patients with late-stage gout, tophi exist in a stable state, referred to as “silent” tophi. However, during clinical tophus removal, the disruption of the structural or functional stability of “silent” tophi often leads to the explosive reactivation of inflammation. Considering these findings, we propose that future therapeutic strategies should focus on the precise modulation of NET dynamics, aiming to maintain immune equilibrium and prevent the recurrence of gout flares.

Authors with CRIS profile

Martin Herrmann Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

Zhejiang University / Chekiang University / 浙江大学 CN China (CN) Second Affiliated Hospital of Zhejiang University (SAHZU) / 浙江大学 医学院 附属第二医院 CN China (CN) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) DE Germany (DE) West China Medical Center of Sichuan University / 四川大学华西医学中心 CN China (CN)

How to cite

APA:

Wang, Y., Han, J., Knopf, J., Zhu, L., Zhao, Y., Liu, L., & Herrmann, M. (2025). NET Formation Drives Tophaceous Gout. Gout, Urate, and Crystal Deposition Disease, 3(3). https://doi.org/10.3390/gucdd3030016

MLA:

Wang, Yuqi, et al. "NET Formation Drives Tophaceous Gout." Gout, Urate, and Crystal Deposition Disease 3.3 (2025).

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