# Spatiotemporal immune gradients in gout: immune response–driven activation of the NLRP3–IL-1β axis and its transition to trained immunity

## TL;DR

This paper explores how the immune system changes over time and space in gout, focusing on inflammation and recovery phases, and proposes new treatment strategies.

## Contribution

The study introduces a spatiotemporal immune framework for gout, linking immune gradients to disease progression and proposing precision intervention strategies.

## Key findings

- Acute gout flares are driven by NLRP3–IL-1β activation and innate immunity.
- Immune resolution involves Tregs, M2 macrophages, and pro-resolving mediators.
- Trained immunity persists during remission with low-grade activation.

## Abstract

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.

(A) Spatiotemporal model of immune responses in gout: The horizontal axis depicts the temporal dimension of gout progression, spanning the acute flare phase, inflammation amplification phase, resolution phase, and remission phase. The vertical axis represents a spatial gradient extending from the local joint to the skeletal system and the systemic circulation. During the flare and amplification phases, the dominant mechanisms are pro-inflammatory cascades mediated by M1-polarized macrophages, Th17 cells, and NETs, accompanied by robust activation of the NLRP3 inflammasome. Upon entry into the resolution phase, immune lineages undergo functional reprogramming, with M2-polarized macrophages, Tregs, and aggNETs driving active inflammation resolution. The remission phase reveals features of “trained immunity, “ primarily involving monocyte and T-cell subsets, characterized by a dynamic immune homeostasis maintained under conditions of low-grade activation. (B) Identification of immune cell subsets and molecular components: This panel provides detailed symbol definitions and terminological annotations for the key immune cell subsets, signaling molecules, and microenvironmental components depicted in the figure. (C) Spatiotemporal framework of gout and stratified intervention strategies: This panel integrates temporal disease evolution with spatial inflammatory gradients in gout. Based on this framework, “time-oriented” strategies targeting distinct inflammatory stages and “space-oriented” precision interventions targeting specific anatomical compartments are proposed, aiming to shift clinical management from global anti-inflammatory approaches to precision intervention. (D) Drug delivery systems and drug conjugation: A schematic illustration of drug delivery systems conjugated with therapeutic agents, enabling targeted delivery to lesion sites to achieve precise intervention and optimized therapeutic efficacy.Multilayered scientific diagram illustrating gout inflammation progression across joint, bone, and circulatory system. Panels display acute flare, resolution, and remission phases, key immune cells and molecules, explanatory text on temporal, spatial, and spatiotemporal dimensions, and a schematic of drug plus delivery systems enabling precision intervention in the human body.

(A) Spatiotemporal model of immune responses in gout: The horizontal axis depicts the temporal dimension of gout progression, spanning the acute flare phase, inflammation amplification phase, resolution phase, and remission phase. The vertical axis represents a spatial gradient extending from the local joint to the skeletal system and the systemic circulation. During the flare and amplification phases, the dominant mechanisms are pro-inflammatory cascades mediated by M1-polarized macrophages, Th17 cells, and NETs, accompanied by robust activation of the NLRP3 inflammasome. Upon entry into the resolution phase, immune lineages undergo functional reprogramming, with M2-polarized macrophages, Tregs, and aggNETs driving active inflammation resolution. The remission phase reveals features of “trained immunity, “ primarily involving monocyte and T-cell subsets, characterized by a dynamic immune homeostasis maintained under conditions of low-grade activation. (B) Identification of immune cell subsets and molecular components: This panel provides detailed symbol definitions and terminological annotations for the key immune cell subsets, signaling molecules, and microenvironmental components depicted in the figure. (C) Spatiotemporal framework of gout and stratified intervention strategies: This panel integrates temporal disease evolution with spatial inflammatory gradients in gout. Based on this framework, “time-oriented” strategies targeting distinct inflammatory stages and “space-oriented” precision interventions targeting specific anatomical compartments are proposed, aiming to shift clinical management from global anti-inflammatory approaches to precision intervention. (D) Drug delivery systems and drug conjugation: A schematic illustration of drug delivery systems conjugated with therapeutic agents, enabling targeted delivery to lesion sites to achieve precise intervention and optimized therapeutic efficacy.