MSU crystals can be phagocytosed by neutrophils and monocytes/macrophages, leading to the activation of the intracellular NLRP3 inflammasome and the release of large amounts of pro-inflammatory mediators (13). Among these cells, macrophages occupy a central position. Evidence indicates that tissue-resident macrophages may initiate and drive the early inflammatory response, whereas recruited monocyte-derived macrophages are more actively involved in the subsequent resolution of inflammation (14). MSU crystals induce metabolic–inflammatory reprogramming in macrophages, involving pathways related to lipid and amino acid metabolism, glycolysis, oxidative stress, and apoptosis (12). Activated macrophages produce cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κB), and key cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6, and IL-18, thereby further amplifying the inflammatory response (12). In addition to phagocytosis, neutrophils contribute to inflammation by undergoing necrosis or forming neutrophil extracellular traps (NETs), releasing MSU crystals and NETs components, which sustain and exacerbate local inflammatory responses (15). In the context of adaptive immunity, T-lymphocyte subsets also play important roles. T helper 17 (Th17) cells promote neutrophil recruitment through the secretion of interleukin-17 (IL-17) in MSU-induced inflammatory environments and are linked to receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis. In contrast, regulatory T cells (Tregs) suppress excessive immune responses by producing anti-inflammatory factors, including IL-4, IL-10, and transforming growth factor-β1 (TGF-β1). Th1 and Th2 cells contribute to immune regulation through the secretion of cytokines such as interferon-γ (IFN-γ), IL-2, and IL-18, and IL-4 and IL-10, respectively. Notably, certain T-cell subsets can also express RANKL, thereby directly promoting osteoclast formation and participating in bone erosion (16). In addition, changes in immune cell growth, differentiation, and functional states profoundly influence the inflammatory course during the acute phase (17).

Activation of the NLRP3 inflammasome represents a central molecular event in MSU crystal–triggered inflammation during the acute phase of gout (4). Acting as danger signals, MSU crystals promote the assembly of the NLRP3 inflammasome, leading to the activation of caspase-1, which subsequently cleaves pro–IL-1β and pro–IL-18 into their biologically active forms, IL-1β and IL-18, thereby initiating and amplifying the inflammatory cascade (18). The signaling regulation of this process involves multiple mechanisms. The signaling regulation of this process involves multiple mechanisms. The generation of reactive oxygen species (ROS) not only directly contributes to the activation of the NLRP3 inflammasome but also influences the activation of related signaling pathways, including nuclear factor erythroid 2–related factor 2 (Nrf2) and the myeloid differentiation primary response 88–nuclear factor-κB (MyD88–NF-κB) axis (17). Notably, uric acid itself, beyond its crystalline form, can potentiate MSU-induced pro-inflammatory responses. Clinical observations indicate that serum IL-1β levels are significantly elevated in patients with hyperuricemia and gout and show a positive correlation with serum urate concentrations, further supporting a critical role for uric acid in inflammasome activation and the pathogenesis of gout (19).

The inflammatory response triggered by MSU is a complex cascade process that involves the coordinated actions of multiple cytokines and inflammatory mediators (20). Among these, cytokines such as IL-1β, IL-6, IL-8, IL-17, IL-18, and TNF-α play central roles in gout-associated inflammation (21). For example, serum levels of IL-1β and IL-9 are significantly elevated in patients with gout and show a positive correlation with serum urate concentrations (19). In addition, chemokines, reactive oxygen species, components of the complement system (such as C-reactive protein), and myeloperoxidase are also broadly involved in, and further amplify, local inflammatory responses (22). Although acute gout flares are typically self-limiting and resolve spontaneously within days to weeks, the resolution of inflammation is not a passive process but instead depends on active regulatory mechanisms. This process involves the production of multiple anti-inflammatory mediators, such as IL-37, which effectively restrains MSU crystal–induced innate immune responses and promotes the resolution of inflammation (23) (Figure 2).

The clinical remission phase does not represent the pathological endpoint of gout. Evidence indicates that MSU crystal deposition in the joint and surrounding tissues persists during remission and continues to provide chronic stimulation to the immune system, driving a state of subclinical inflammation that underlies disease recurrence and chronic progression (24). Deposited MSU crystals can be recognized and phagocytosed by immune cells such as tissue-resident macrophages. This process sustains intracellular NLRP3 inflammasome activation and maintains a local pro-inflammatory milieu at a low level (25). This chronic stimulation, together with its precursor soluble uric acid, may induce persistent functional and epigenetic reprogramming of innate immune cells. Seminal studies have demonstrated that soluble uric acid can “train” primary human monocytes, enabling them to mount enhanced inflammatory responses, including increased IL-1β production, upon subsequent stimulation, through specific epigenetic regulatory mechanisms (26). Based on such evidence, a theoretical framework has been proposed suggesting that a “trained immunity–like” state may exist in gout (27). This state is thought to lower the activation threshold of the immune system, thereby providing a molecular-level hypothesis to explain the propensity for recurrent acute gout flares (28). This renders the immune system more sensitive to subsequent crystal stimuli and lowers the response threshold, providing a potential molecular-level explanation for the recurrent nature of acute gout flares (25).

During the remission phase, the persistent deposition of MSU crystals drives phenotypic and functional remodeling of immune cells, forming the cellular basis of subclinical inflammation and the risk of disease recurrence. monocytes/macrophages do not revert to a fully resting state during remission. Instead, the NLRP3 inflammasome pathway remains at a low level of activation, leading to sustained production of pro-inflammatory mediators. Single-cell transcriptomic studies suggest that this persistent low-grade activation is accompanied by remodeling of cellular phenotypes (6). Within the theoretical framework of trained immunity, this state is thought to render immune cells more responsive to subsequent stimuli, thereby potentially increasing the risk of disease recurrence (27, 29). At the same time, although neutrophils do not infiltrate in large numbers as observed during the acute phase, they can still contribute through low-level NETosis, releasing residual crystals and pro-inflammatory mediators that help maintain the local inflammatory microenvironment within the joint (15, 30). The adaptive immune system also undergoes key alterations. Single-cell RNA sequencing (scRNA-seq) analyses have demonstrated the presence of MSU crystal–associated, disease-specific transcriptomic changes in peripheral blood mononuclear cells (PBMCs) from patients during the remission phase (24). Among these changes, the balance between pro-inflammatory Th17 cells and anti-inflammatory Tregs is critical. Th17 cells exacerbate inflammation and may drive bone erosion through the secretion of cytokines such as IL-17, whereas Tregs attempt to restrain immune responses by producing IL-10 and TGF-β1. Disruption of this balance represents a key step in the transition from remission to disease relapse (16). More recent studies further reveal that the suppressed state of specific lymphocyte subsets, such as Vδ2 T cells, is closely associated with stable clinical remission and may serve as a potential biomarker for predicting disease recurrence (31). In addition, the contribution of B cell–mediated humoral immunity has increasingly attracted attention, as it may participate in chronic inflammatory processes through the production of autoantibodies (32). This crystal-driven chronic stimulation, leading to widespread activation and dysregulation of both the innate and adaptive immune systems, collectively defines the unstable immunological state characteristic of the remission phase of gout.

The clinical remission phase of gout essentially represents a state of subclinical immune activation shaped by trained immunity. In this state, immune cells maintain a “pre-activated” phenotype even after the initial stimuli have subsided, enabling a faster and more robust response to subsequent danger signals, such as MSU crystals (33). Similar mechanisms have been described in inflammatory arthritis, where pronounced immune cell dynamics can still be observed during remission and are closely linked to the risk of disease relapse (34). In the context of gout, the persistent presence of MSU crystals, fluctuations in local joint pH and temperature, or concomitant infectious events may all serve as secondary stimuli. When the intensity of these stimuli exceeds the individualized immune relapse threshold shaped by trained immunity, an uncontrolled inflammatory cascade is rapidly initiated, resulting in an acute flare. Accordingly, the remission phase of gout can be viewed as a “threshold period” characterized by the dynamic accumulation of relapse risk (35).

The resolution of inflammation during the remission phase of gout is not a state of passive quiescence but rather an active and programmed biological process, centered on restoring immune microenvironmental homeostasis and initiating tissue repair (36). Following an acute flare, the host activates a series of intrinsic pro-resolving mechanisms to precisely terminate inflammatory responses. These mechanisms include the downregulation of key pro-inflammatory signaling pathways, such as NF-κB; the biosynthesis of bioactive specialized pro-resolving lipid mediators (SPMs), including lipoxins, protectins, resolvins, and maresins; the generation of non-lipid pro-resolving mediators; the efficient clearance of apoptotic cells and debris through efferocytosis; and the induction of immunoregulatory Tregs (37). For example, the local production of anti-inflammatory cytokines such as IL-10 and Annexin A1 (ANXA1) effectively suppresses further neutrophil chemotaxis and infiltration, thereby actively promoting the resolution of inflammation (38). However, during the remission phase of gout, this finely tuned resolution program may not be fully or durably restored. Insufficient activation or premature termination of these pathways can result in incomplete resolution, allowing local or systemic tissues to remain in a state of chronic, low-grade inflammation. Such an “unresolved” microenvironment may not only directly contribute to ongoing tissue damage but is also thought to increase susceptibility to acute gout flares, thereby driving the recurrent cycle of flare and remission.

In summary, chronic stimulation by MSU crystals may induce persistent functional and epigenetic reprogramming of innate immune cells, resulting in the establishment of trained immunity. This concept provides a novel and coherent theoretical framework for understanding sustained subclinical inflammation during the remission phase of gout and the high propensity for recurrent acute flares (27, 29). However, it must be emphasized that, although this hypothesis is mechanistically plausible and supported by analogous evidence from other chronic inflammatory diseases (39, 40), direct functional evidence in human gout remains in an emerging stage. Future longitudinal studies are required to determine whether immune cells from patients with gout harbor canonical epigenetic signatures and metabolic features of trained immunity, and to clarify their direct causal relationship with disease relapse. Distinguishing robust theoretical hypotheses from human phenomena that remain to be directly validated will be essential for guiding future translational research (Figure 3).

In the early stage of an acute gout flare, MSU crystals are initially recognized by synovial monocytes/macrophages. This recognition activates the NF-κB pathway through pattern recognition receptors, including Toll-like receptor 2/4 (TLR2/4) and C-type lectin domain family 12 member A (CLEC12A), thereby providing a “priming” signal for NLRP3 inflammasome assembly (41, 42). Once assembled, the NLRP3 inflammasome induces robust production and release of IL-1β (43, 44). As an immediate innate immune cytokine, IL-1β is critical for initiating host defense responses and further promotes the release of multiple inflammatory mediators (45). At this stage, innate immune cells, including macrophages and neutrophils, are rapidly recruited to the inflamed site, and the sharp increase in IL-1β levels drives severe joint pain and inflammatory responses (46). Studies show that MSU crystals stimulate monocytes/macrophages to secrete IL-1β and TNF-α (47). MSU simultaneously activates the complement system, and the generated C3a and C5a, together with chemokines such as CXCL8/IL-8 and CCL2, cooperatively promote massive neutrophil infiltration (48, 49). This stage is characterized by an IL-1β–centered innate immune response, amplified through the coordinated actions of M1-polarized macrophages and neutrophils. Clinically, antibodies targeting IL-1β, such as canakinumab, are effective in the treatment of acute gouty arthritis (50, 51) (Figures 4A, B, F, G).

As the inflammation amplification phase ensues, neutrophil infiltration reaches its peak, and the proportion of polymorphonuclear cells in synovial fluid increases markedly (41). Activated neutrophils undergo degranulation, generate ROS, and release proteolytic enzymes, thereby further damaging local tissues; NETs formed at this stage display pronounced pro-inflammatory properties (52). In parallel, monocytes/macrophages sustain NLRP3 inflammasome activation, continue to produce IL-1β, and exhibit a characteristic M1-polarized phenotype (14, 53, 54).

During this period, T cells also play a prominent role, with Th17 cells becoming particularly active (55). Th17 cells differentiate and mature under the influence of cytokines such as IL-1β, IL-6, and TGF-β (56), and subsequently secrete cytokines including IL-17, IL-21, and IL-22 (57). IL-17 can further promote inflammatory responses, thereby sustaining and amplifying inflammatory signaling (58). Specifically, IL-17 stimulates fibroblasts, endothelial cells, and macrophages to release chemokines such as CXCL8/IL-8 and granulocyte–macrophage colony-stimulating factor (GM-CSF), maintaining neutrophil recruitment and forming a positive feedback loop with the NLRP3–IL-1β axis (59) (Figures 4C, F, G).

A hallmark of acute gouty arthritis is its tendency to resolve spontaneously within 7–10 days, reflecting the presence of intrinsic inflammatory resolution mechanisms (60). During this phase, large numbers of neutrophils undergo apoptosis and are cleared by macrophages through efferocytosis, driving macrophage polarization from an M1 to an M2 phenotype. M2-polarized macrophages release IL-10, TGF-β, and pro-resolving lipid mediators, thereby suppressing NLRP3 inflammasome activation and promoting tissue repair (61).

At this stage, Tregs play a pivotal role by suppressing inflammatory responses and restoring immune balance through the secretion of immunosuppressive cytokines, including IL-10 and TGF-β. IL-10 is a key anti-inflammatory cytokine that effectively inhibits IL-1β production, and Tregs restrain Th17 cell–mediated inflammation through IL-10–dependent signaling, thereby facilitating the resolution of inflammation (62). At the same time, activated polymorphonuclear neutrophils (PMNs) release NETs, which can entrap MSU crystals and form NET–MSU aggregates. These NET–MSU aggregates are capable of degrading cytokines and chemokines and blocking further neutrophil recruitment and activation, thereby promoting the resolution of gouty inflammation (63, 64). The functional shift of NETs from an early pro-inflammatory role to a later pro-resolving role, together with the coordinated actions of M2-polarized macrophages and Tregs, helps explain the self-limiting nature of acute gouty inflammation (60, 65). In addition, lipid mediator profiling indicates that prostaglandins and leukotrienes predominate in the early phase, whereas resolvins, lipoxins, protectins, and maresins increase during the later phase, giving rise to “lipid mediator class switching, “ which facilitates the termination of inflammation (27, 29) (Figures 4D, F, G).

Even after entering clinical remission, the immune system does not become fully “quiescent”. Single-cell transcriptomic studies reveal that, compared with the acute phase, patients in remission exhibit marked changes in the composition of peripheral blood monocyte subsets and the proportion of Tregs, reflecting a state of persistent low-grade activation with features of trained immunity (6). Under conditions of sustained hyperuricemia, monocytes/macrophages are further driven to undergo metabolic and epigenetic reprogramming (66). Based on studies specifically addressing uric acid–induced immune programming, this process may drive the acquisition of a trained immunity phenotype, enabling a heightened inflammatory response upon re-exposure to MSU (27, 29). Accordingly, trained immunity has been proposed as a theoretically attractive potential mechanism underlying the propensity for clinical relapse in gout. Epidemiological studies indicate that gout recurrence is positively correlated with serum urate levels (67). Therefore, to reduce the likelihood of recurrent acute flares, serum urate should be maintained at low levels during the remission phase (Figures 4E–G).

Intra-articular inflammation is not uniform but instead exhibits a complex spatial distribution, which not only influences disease progression but also provides an additional dimension for mechanistic investigation (69). In gouty arthritis, the synovium represents a key site of inflammatory initiation (70). MSU crystals activate synovial macrophages, neutrophils, and T lymphocytes, accompanied by the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 (10). These factors are associated with synovitis, synovial hyperplasia, and angiogenesis in inflammatory joint diseases (71, 72). Cartilage, as a critical structural component of the joint, is also commonly affected by damage in gout (73, 74). Inflammatory mediators and matrix metalloproteinases (MMPs) released by activated synovial cells and chondrocytes drive degradation of the cartilage matrix (73). Such cartilage damage is typically more pronounced in regions with MSU crystal deposition, indicating spatial heterogeneity of local inflammation (74). These differences can be detected using imaging modalities. Ultrasound (US) enables the detection of periarticular MSU deposition, synovitis, and bone erosion (75, 76). Dual-energy computed tomography (DECT) can identify tophus deposition and assess intra-articular bone lesions (77, 78). Magnetic resonance imaging (MRI) is used to evaluate inflammation, bone erosion, and cartilage damage. Together, these imaging techniques reveal the fine spatial distribution of gouty lesions within the joint, reflecting the focal deposition of MSU crystals on the articular cartilage surface and within the synovium (79).

These imaging modalities provide macroscopic spatial information, whereas spatial transcriptomics enables the interrogation of tissue-intrinsic spatial heterogeneity at the cellular and molecular levels (80, 81). Although direct spatial transcriptomic data from gouty synovial tissue are still emerging, single-cell studies of peripheral blood and synovial fluid have already uncovered clues to the spatial heterogeneity of immune responses. For example, evidence indicates that even during clinical remission, MSU crystal deposition continues to drive both local and systemic immune responses (24). A single-cell sequencing study of peripheral blood mononuclear cells from patients with gout identified a distinct pro-inflammatory monocyte subset present during remission, whose transcriptomic profile is associated with a systemic inflammatory state (6). More detailed investigations in patients in remission with MSU crystal deposition further demonstrate that crystal deposits directly contribute to shaping the local immune microenvironment, indicating a high degree of spatial specificity in immune cell infiltration and activation within the joint (24). Collectively, these findings suggest that intra-articular inflammation in gout is not diffuse or uniform but instead is organized around sites of crystal deposition, forming a spatial immune gradient mediated by specific immune cell subsets across molecular, cellular, and tissue levels (Table 1; Figure 5A).

Gout not only affects articular cartilage but also extends to the subchondral bone, ultimately manifesting as bone destruction and erosion (82, 83). From the perspective of osteo–immune interactions, MSU crystals deposited on joint and bone surfaces enhance the activity of the RANKL–osteoclast axis. In addition, certain T cell subsets, upon inflammatory stimulation, secrete RANKL, thereby promoting osteoclast differentiation and activation. Concurrently, pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-17 create a local immunoinflammatory “hotspot, “ which further exacerbates osteoclastogenesis and bone resorption (16). On the one hand, these upregulated inflammatory factors are enriched in pathways related to bone metabolism; in gout patients in remission with persistent MSU crystal deposition, elevated inflammatory mediators may directly participate in processes of bone destruction. On the other hand, monocytes migrating into joints with MSU crystal deposition can differentiate into osteoclasts under inflammatory conditions and the combined influences described above, thereby contributing to bone resorption (84) (Figure 5B).

The circulation serves as a critical bridge linking local joint inflammation with systemic immune status by mediating the transport of inflammatory cytokines and molecular signals (85). Even during clinical remission, the systemic immune state of patients with gout does not fully subside. Single-cell transcriptomic analyses provide supportive evidence for this notion: during remission, peripheral blood from patients with gout harbors monocyte subsets with distinct transcriptomic profiles, and both the proportion and functional state of Tregs differ significantly from those observed in healthy controls or in patients during the acute phase (6). In addition, another study further reveals that MSU crystal deposition itself can continuously drive transcriptional reprogramming across multiple immune cell types. Such systemic signals may originate from the local joint microenvironment and propagate throughout the body via circulating immune cells (24). Together, these data support the existence of an immune activation gradient that is transmitted from local crystal deposition sites to the systemic circulation (24, 68).

This systemic state of immune activation constitutes a shared inflammatory basis between gout and multiple comorbid conditions. Given the similarities in immune mechanisms across inflammatory diseases, the persistent activation of peripheral immune cells described above may be closely linked to the high prevalence of cardiometabolic disorders and diabetes observed in patients with gout (86, 87). At the same time, T cell activation plays an important role in the inflammatory responses associated with myocardial ischemia–reperfusion injury, coronary atherosclerotic heart disease, obesity, and diabetes (88, 89). Beyond metabolic disorders, chronic kidney disease is also closely linked to gout (90). On the other hand, chemokines present in the circulation can promote the recruitment of immune cells and inflammatory signals to the joint, thereby triggering local inflammatory responses (91). This indicates that local joint inflammation and systemic immune responses are interconnected through the circulation (Figures 5C, D).

The emergence of this spatial immune gradient–associated pattern is rooted in molecular differences in how distinct tissue microenvironments respond to MSU crystals. Within the joint cavity, high local concentrations of MSU directly initiate a canonical innate immune response centered on the NLRP3 inflammasome and the IL-1β axis (17). Concurrently, locally produced chemokines generate concentration gradients that precisely direct the routes of immune cell infiltration (91). In addition, emerging perspectives on neuro–immune interactions warrant attention. Although evidence in gout is still accumulating, sensory nerve endings that detect crystal deposition and pain may release neuropeptides and related mediators, thereby retrogradely modulating local vascular permeability and immune cell function and contributing to the shaping of a three-dimensional inflammatory spatial architecture (92, 93). Overall, immune responses in gout exhibit multi-layered spatial differences and interconnections across the joint, bone, and Circulation. Elucidating these patterns is of critical importance for the development of precision intervention strategies that target specific disease sites, such as the synovium or the bone, as well as for the use of circulating biomarkers in disease staging and prognostic assessment.