REVIEW article
Front. Immunol.
Sec. Inflammation
Spatiotemporal Immune Gradients in Gout: Immune Response–Driven Activation of the NLRP3–IL-1β Axis and Its Transition to Trained Immunity
Provisionally accepted
- 1The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- 2School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- 3Huaihua City Hospital of Traditional Chinese Medicine, Huaihua, China
- 4The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, China
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Gout is a crystal-associated autoinflammatory disease triggered by monosodium urate (MSU) crystals, clinically characterized by recurrent transitions between acute inflammatory flares dominated by innate immunity and a state of "trained immunity" during the remission phase. However, previous studies have mostly focused on single time points or local lesions. Such approaches fail to systematically explain the recurrent nature of acute gout flares and the mechanisms underlying multi‑system involvement. By integrating evidence from single-cell and spatial transcriptomics as well as mechanistic investigations, this review systematically summarizes the immunopathological features of gout within a spatiotemporal immune framework. At the temporal level, acute gout flares are driven by innate immune activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3)–interleukin-1β (IL-1β) inflammatory cascade. The inflammation then undergoes self-limited resolution mediated by regulatory T cells (Tregs), M2-polarized macrophages, aggregated neutrophil extracellular traps (aggNETs), and pro-resolving lipid mediators. persistent low-grade activation of monocytes/macrophages can still be observed, sustaining a state of "trained immunity." At the spatial level, integrated evidence indicates an immune gradient across the joint, bone, and circulation, ranging from focal hyper-inflammation to systemic low-grade activation. Based on these findings, we propose a time-window stratified intervention strategy centered on the NLRP3–IL-1β axis, and identify inflammatory markers in the joints, subchondral bone, and peripheral blood as the basis for spatially targeted stratification. These insights provide novel perspectives for shifting gout management from the control of individual flares to recurrence risk management and personalized therapy.
Keywords: Gout, immune response, Inflammatory Response, precision therapy, spatiotemporal immune gradient, trained immunity
Received: 27 Dec 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 wang, li, Li, Zeng, li, chen and xiong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
pei chen
hui xiong
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