Molecular Pathophysiology of Gout

doi:10.1016/j.molmed.2017.06.005

Trends in Molecular Medicine

Volume 23, Issue 8, August 2017, Pages 756-768

https://doi.org/10.1016/j.molmed.2017.06.005 Get rights and content

Trends

The early phase of acute gouty arthritis is characterized by an auto-amplification loop of regulated necrosis and inflammation; MSU crystals trigger both cell necrosis and inflammation in a direct as well as indirect manner.

The later phase of gouty arthritis is characterized by the resolution of symptoms despite persistence of MSU crystals. Numerous immunoregulatory pathways as well as aggregated neutrophil extracellular traps contribute to this process.

Chronic gout is characterized by tophus formation; that is, masses of MSU crystals and NETs encapsulated by a foreign body reaction involving giant cells, macrophages, and fibroblasts that contribute to the destruction of surrounding tissues.

Dissecting the molecular and cellular pathogenesis of gout can help to identify innovative drug targets.

Three contradictory clinical presentations of gout have puzzled clinicians and basic scientists for some time: first, the crescendo of sterile inflammation in acute gouty arthritis; second, its spontaneous resolution, despite monosodium urate (MSU) crystal persistence in the synovium; and third, immune anergy to MSU crystal masses observed in tophaceous or visceral gout. Here, we provide an update on the molecular pathophysiology of these gout manifestations, namely, how MSU crystals can trigger the auto-amplification loop of necroinflammation underlying the crescendo of acute gouty arthritis. We also discuss new findings, such as how aggregating neutrophil extracellular traps (NETs) might drive the resolution of arthritis and how these structures, together with granuloma formation, might support immune anergy, but yet promote tissue damage and remodeling during tophaceous gout.

Section snippets

Towards an Increased Understanding of Necroinflammation in Gout

Gout presents most commonly as acute episodic arthritis in patients, while the symptoms and signs of visceral and chronic gout (see Glossary) are less well defined [1]. The symptoms of an acute attack of gouty arthritis include articular and/or periarticular swelling and inflammation in joint with rapid onset (12–24 h), whereas chronic gout develops after some years of recurrent acute gout attacks, leading to pain and stiffness due to progressive tissue destruction [2]. Guidelines based on

Clinical Presentations of Gout

The most frequent clinical presentation of gout in humans is the presence of recurrent episodes of acute arthritis involving one joint at a time [3]. By contrast, tophaceous and visceral gout are characterized by the formation of tophi, which are abscess-like creamy masses comprising MSU crystals and dead immune cells. The clinical features of intermittent acute gout and chronic gout are described below.

The Crescendo of Acute Gouty Arthritis: The Necroinflammation Loop

Acute gouty arthritis is triggered by MSU crystals inside joints, a process promoted by a local imbalance of uric acid supersaturation as well as potential pre-existing structural joint damage, such as osteoarthritis [1] (Figure 1, Key Figure).

The Decrescendo of Acute Gouty Arthritis: Counter-Regulation of Sterile Inflammation

If not counter-regulated, the crescendo of acute inflammation has the potential to end in a cytokine storm, systemic clotting, organ failure, and death. As described below, the crescendo of crystal-induced necroinflammation involves the subsequent activation of numerous immunoregulatory elements that limit necroinflammation and promote the resolution of the acute inflammatory response (Figure 2A).

Anergic Tophi: Crystal Masses Devoid of Inflammation

In contrast to acute gout, the mechanisms of chronic tophaceous gout are less well understood. Chronic gout is characterized by the formation of tophi in joints, skin, or bursae that resemble chronic granulomatous lesions containing MSU crystal-NET masses at the center surrounded by mono- and multinucleated phagocytes (‘giant cells’) and fibroblasts (Figure 2B) [99]. The tophus comprises three central compartments: (i) a central crystalline core formed of MSU crystals; (ii) a surrounding area

Concluding Remarks

Acute gouty arthritis is a paradigmatic example of the crescendo and decrescendo of crystal-induced necroinflammation. Understanding the role of IL-1 in the molecular pathogenesis of gout has raised the possibility of using IL-1-targeting drugs as a novel treatment option for patients with recurrent gout. The recent discovery of crystal-induced cytotoxicity offers additional drug targets. Chronic gout is possibly an underdiagnosed disease entity, which can now be spotted with dual-energy

Acknowledgments

We apologize to all colleagues whose work could not be cited or discussed in detail due to space and format restrictions. This work was supported by grants from the Deutsche Forschungsgemeinschaft to H.J.A. (AN372/14-3, 16-1, 20-1, and 24-1) and to S.S. (STE2437/2-1).

Glossary

Aggregated neutrophil extracellular traps (aggNETs): aggregated masses of MSU crystals and NETs that can trap and degrade proinflammatory cytokines and chemokines, thereby contributing to the resolution of inflammation.
Complement factors: several small proteins that enhance the phagocytic function and induce inflammatory responses in innate immunity.
Crystals: a crystal is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a specific microscopic structure. MSU

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Owing to renal reabsorption and the loss of uricase activity, uric acid (UA) is strictly maintained at a higher physiological level in humans than in other mammals, which provides a survival advantage during evolution but increases susceptibility to certain diseases such as gout. Although monosodium urate (MSU) crystal precipitation has been detected in different tissues of patients as a trigger for disease, the pathological role of soluble UA remains controversial due to the lack of causality in the clinical setting. Abnormal elevation or reduction of UA levels has been linked to some of pathological status, also known as U-shaped association, implying that the physiological levels of UA regulated by multiple enzymes and transporters are crucial for the maintenance of health. In addition, the protective potential of UA has also been proposed in aging and some diseases. Therefore, the role of UA as a double-edged sword in humans is determined by its physiological or non-physiological levels. In this review, we summarize biosynthesis, membrane transport, and physiological functions of UA. Then, we discuss the pathological involvement of hyperuricemia and hypouricemia as well as the underlying mechanisms by which UA at abnormal levels regulates the onset and progression of diseases. Finally, pharmacological strategies for urate-lowering therapy (ULT) are introduced, and current challenges in UA study and future perspectives are also described.
Protocol to create a murine subcutaneous air pouch for the study of monosodium urate crystal-induced gout
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Monosodium urate (MSU) crystal deposition in articular joints and bursal tissue causes acute joint inflammation, which is a hallmark of gout. Here, we describe the steps necessary to create a subcutaneous air pouch on the back of mice that resembles this bursa-like space with a synovial lining-like membrane. We then detail the injection of MSU crystals into this pouch, which induces a localized inflammatory response reminiscent of gout and approaches to quantify the inflammatory response.
For complete details on the use and execution of this protocol, please refer to Devi et al. (2023),¹ de Almeida et al. (2022),² and Ratsimandresy et al. (2017).³
Geraniin restricts inflammasome activation and macrophage pyroptosis by preventing the interaction between ASC and NLRP3 to exert anti-inflammatory effects
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Geraniin, a chemical component of the traditional Chinese medicine geranii herba, possesses anti-inflammatory and anti-oxidative activities. However, its anti-inflammatory role in managing NLRP3 inflammasome and pyroptosis remains to be elucidated. To investigate the anti-inflammation mechanism of geraniin, LPS-primed macrophages were incubated with classical activators of NLRP3 inflammasome (such as ATP, Nigericin, or MSU crystals), and MSU crystals were injected into the ankle joints of mice to establish an acute gouty arthritis model. The propidium iodide (PI) staining results showed that geraniin could restrain cell death in the ATP- or nigericin-stimulated bone marrow-derived macrophages (BMDMs). Geraniin decreased the release of lactate dehydrogenase (LDH) and interleukin (IL)-1β from cytoplasm to cell supernatant. Geraniin also inhibited the expression of caspase-1 p20, IL-1β in cell supernatant and N-terminal of gasdermin D (GSDMD-NT) while blocking the oligomerization of ASC to form speck. The inhibitory effects of geraniin on caspase-1 p20, IL-1β, GSDMD-NT, and ASC speck were not observed in NLRP3 knockout (NLRP3^-/-) BMDMs. Hence, the resistance of geraniin to inflammasome and pyroptosis was contingent upon NLRP3 presence. Geraniin reduced reactive oxygen species (ROS) production and maintained mitochondrial membrane potential while preventing interaction between ASC and NLRP3 protein. Additionally, geraniin diminished MSU crystal-induced mouse ankle joint swelling and IL-1β expression. Geraniin blocked the recruitment of neutrophils and macrophages to the synovium of joints. Our results demonstrate that geraniin prevents the assembly of ASC and NLRP3 through its antioxidant effect, thereby inhibiting inflammasome activation, pyroptosis, and IL-1β release to provide potential insights for gouty arthritis targeted therapy.
The acute spinal cord injury microenvironment and its impact on the homing of mesenchymal stem cells
2024, Experimental Neurology
Spinal cord injury (SCI) is a highly debilitating condition that inflicts devastating harm on the lives of affected individuals, underscoring the urgent need for effective treatments. By activating inflammatory cells and releasing inflammatory factors, the secondary injury response creates an inflammatory microenvironment that ultimately determines whether neurons will undergo necrosis or regeneration. In recent years, mesenchymal stem cells (MSCs) have garnered increasing attention for their therapeutic potential in SCI. MSCs not only possess multipotent differentiation capabilities but also have homing abilities, making them valuable as carriers and mediators of therapeutic agents. The inflammatory microenvironment induced by SCI recruits MSCs to the site of injury through the release of various cytokines, chemokines, adhesion molecules, and enzymes. However, this mechanism has not been previously reported. Thus, a comprehensive exploration of the molecular mechanisms and cellular behaviors underlying the interplay between the inflammatory microenvironment and MSC homing is crucial. Such insights have the potential to provide a better understanding of how to harness the therapeutic potential of MSCs in treating inflammatory diseases and facilitating injury repair. This review aims to delve into the formation of the inflammatory microenvironment and how it influences the homing of MSCs.
Association between the dietary inflammatory index and gout in the National Health and Nutrition Examination Survey 2007–2018
2023, Heliyon
The aim of our study was to investigate whether the Dietary Inflammatory Index (DII) correlated with gout in American adults.
The study used data from the 2007–2018 National Health and Nutrition Examination Survey, with 27,710 adults participating. Initially, multivariable analysis was performed, with controls for covariates, to assess the link of DII and gout. Then, restricted cubic splines (RCS) were applied to model the nonlinear relationship of DII and gout. Furthermore, propensity score matching (PSM) as a further study of potential relationships was established. Eventually, subgroup analysis was performed.
Participants within the highest DII quartile would be more susceptible to increased risk of gout in the univariate regression model (Q4 vs. Q1, OR = 1.31, CI: 1.05–1.63). Additionally, a positive correlation was detected between gout risk and DII after adjusting on drinking, smoking, gender, race, age, and BMI. Based on RCS analysis, we observed that the risk of gout raised sharply as DII values increased, then flattened, and increased sharply again when the DII was greater than approximately 2.5. After performing the PSM, it was observed that DII correlated in a positive way to the presence of gout on a fully adjusted multivariable model. Subgroup analysis revealed that the link of DII and gout showed no statistical significance in females, blacks, Mexicans, nor in the population that smoked.
Greater degrees of pro-inflammation correlate with a higher risk of gout and might be a predisposing factor for gout. Hence, tactics fostering an anti-inflammatory diet for preventing and improving gout in adults should be regarded.
MSU crystal deposition contributes to inflammation and immune responses in gout remission
2023, Cell Reports
As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterize the transcription profiling of peripheral blood mononuclear cells (PBMCs) among intercritical remission gout, advanced remission gout, and normal controls. We find systemic inflammation in gout remission with MSU crystal deposition at the intercritical and advanced stages, evidenced by activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity. We also find increased HLA-DQA1^high classic monocytes and PTGS2^high monocytes in advanced gout and overactivated CD8⁺ T cell subtypes in intercritical and advanced gout. Additionally, the osteoclast differentiation pathway is significantly enriched in monocytes, T cells, and B cells from advanced gout. Overall, we demonstrate systemic inflammation and distinctive immune responses in gout remission with MSU crystal deposition, allowing further exploration of the underlying mechanism and clinical significance in conversion from intercritical to advanced stage.

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^†: These authors contributed equally.

^@: Twitter: @Crystallopathy

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Trends in Molecular Medicine

ReviewMolecular Pathophysiology of Gout

Trends

Section snippets

Towards an Increased Understanding of Necroinflammation in Gout

Clinical Presentations of Gout

The Crescendo of Acute Gouty Arthritis: The Necroinflammation Loop

The Decrescendo of Acute Gouty Arthritis: Counter-Regulation of Sterile Inflammation

Anergic Tophi: Crystal Masses Devoid of Inflammation

Concluding Remarks

Acknowledgments

Glossary

Clin. Med. (Lond.)

Clin. Geriatr. Med.

Immunity

J. Biol. Chem.

Lancet

Mol. Immunol.

Mol. Cell

Immunol. Today

Biochem. Biophys. Res. Commun.

Curr. Biol.

Life Sci.

Trends Immunol.

Immunity

Curr. Opin. Immunol.

Arthritis Rheum.

J. Biol. Chem.

Blood

Prostaglandins Leukot. Essent. Fatty Acids

Immunity

Am. J. Clin. Nutr.

Clinical practice. Gout

N. Engl. J. Med.

Acute monoarthritis: what is the cause of my patient’s painful swollen joint?

Can. Med. Assoc. J.

Application of a novel diagnostic rule in the differential diagnosis between acute gouty arthritis and septic arthritis

J. Korean Med. Sci.

The gouty tophus: a review

Curr. Rheumatol. Rep.

Monosodium urate crystals induce oxidative stress in human synoviocytes

Arthritis Res. Ther.

Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Nat. Commun.

Regulated necrosis: the expanding network of non-apoptotic cell death pathways

Nat. Rev. Mol. Cell Biol.

Necrosome core machinery: MLKL

Cell. Mol. Life Sci.

Crystal formation in inflammation

Annu. Rev. Immunol.

New aspects of the pathogenesis of gout Danger signals, autoinflammation and beyond

Z. Rheumatol.

Gout-associated uric acid crystals activate the NALP3 inflammasome

Nature

Inflammasomes in health and disease

Nature

NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux

Nature

NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component

Nat. Immunol.

Monosodium urate monohydrate crystal-recruited noninflammatory monocytes differentiate into M1-like proinflammatory macrophages in a peritoneal murine model of gout

Arthritis Rheum.

The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1

N. Engl. J. Med.

Activation of NLRP3 inflammasome by crystalline structures via cell surface contact

Sci. Rep.

Contribution of mast cell-derived interleukin-1beta to uric acid crystal-induced acute arthritis in mice

Arthritis Rheumatol.

Neutrophils and neutrophil extracellular traps orchestrate initiation and resolution of inflammation

Clin. Exp. Rheumatol.

PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling

Eur. J. Immunol.

Activation of PAD4 in NET formation

Front. Immunol.

NETosis and NADPH oxidase: at the intersection of host defense, inflammation, and injury

Front. Immunol.

New insights into neutrophil extracellular traps: mechanisms of formation and role in inflammation

Front. Immunol.

P2Y6 receptor antagonist MRS2578 inhibits neutrophil activation and aggregated neutrophil extracellular trap formation induced by gout-associated monosodium urate crystals

J. Immunol.

Review
Molecular Pathophysiology of Gout