Lower Temperatures Exacerbate NLRP3 Inflammasome Activation by Promoting Monosodium Urate Crystallization, Causing Gout.
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ABSTRACT:
SUBMITTER: Ahn H
PROVIDER: S-EPMC8394355 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGout is usually found in patients with atrial fibrillation (AF). K+ efflux is a common trigger of NLRP3 inflammasome activation which is involved in the pathogenesis of AF. We investigated the role of the K+ channel Kv1.5 in monosodium urate crystal (MSU)-induced activation of the NLRP3 inflammasome and electrical remodeling in mouse and human macrophages J774.1 and THP-1, and mouse atrial myocytes HL-1.Methods and resultsMacrophages, primed with lipopolysaccharide (LPS), were stimulated by MSU. HL-1 cells were incubated with the conditioned medium (CM) from MSU-stimulated macrophages. Western blot, ELISA and patch clamp were used. MSU induced caspase-1 expression in LPS-primed J774.1 cells and IL-1β secretion, suggesting NLRP3 inflammasome activation. A selective Kv1.5 inhibitor, diphenyl phosphine oxide-1 (DPO-1), and siRNAs against Kv1.5 suppressed the levels of caspase-1 and IL-1β. MSU reduced intracellular K+ concentration which was prevented by DPO-1 and siRNAs against Kv1.5. MSU increased expression of Hsp70, and Kv1.5 on the plasma membrane. siRNAs against Hsp70 were suppressed but heat shock increased the expression of Hsp70, caspase-1, IL-1β, and Kv1.5 in MSU-stimulated J774.1 cells. The CM from MSU-stimulated macrophages enhanced the expression of caspase-1, IL-1β and Kv1.5 with increased Kv1.5-mediated currents that shortened action potential duration in HL-1 cells. These responses were abolished by DPO-1 and a siRNA against Kv1.5.ConclusionsKv1.5 regulates MSU-induced activation of NLRP3 inflammasome in macrophages. MSUrelated activation of NLRP3 inflammasome and electrical remodeling in HL-1 cells are via macrophages. Kv1.5 may have therapeutic value for diseases related to gout-induced activation of the NLRP3 inflammsome, including AF.
| S-EPMC9270276 | biostudies-literature
Project description:Regulatory T cells induced by B cells (Treg-of-B cells), a distinct Foxp3- Treg cell subset, have established the roles in the suppression of inflammatory conditions, including asthma and intestinal inflammation. However, little is known about the regulatory effects of Treg-of-B cells on innate immunity. Herein, we examined whether Treg-of-B cells could regulate macrophage function and prevent NLRP3-associated diseases, particularly inflammatory gouty arthritis. Treg-of-B cells, but not thymus-derived Treg or effector T cells, inhibited inflammasome-mediated IL-1β secretion, caspase-1 activation, and NLRP3 production by LPS/ATP stimulation in a cell contact-dependent manner. In addition, Treg-of-B cells inhibited monosodium urate-induced NLRP3 inflammasome activation in vitro via NF-κB signaling. Treg-of-B cells ameliorated gouty inflammation in a mouse air pouch model by reducing neutrophil and leukocyte influx and cytokine and chemokine production. Our results demonstrated that Treg-of-B cells exerted regulatory effects on innate immunity by suppressing NLRP3 inflammasome activation and feasible for future therapeutic applications.
| S-EPMC7881254 | biostudies-literature
Project description:BackgroundUltrasound (US) has a high sensitivity in detecting monosodium urate (MSU) deposition in gout patients. However, the value of US in predicting gout flares has been reported only in a few monocentric studies.ObjectiveTo investigate the association between gout flares in the previous year and US-detected MSU burden using two different US scores.DesignA retrospective study.MethodsPatients with gout were consecutively recruited to undergo musculoskeletal US examinations of their knees, ankles, and feet. The score derived from Outcome Measure in Rheumatology (hereinafter referred to as MSU score) and musculoskeletal US features-based (hereinafter referred to as MSKF score) were used to quantify the MSU burden of gout. Odds ratios for frequent gout flares were calculated.ResultsWe enrolled 1894 patients with gout (mean age: 45 years; gout duration: 5 years; males: 96.1%), experiencing a median of three flares over the past year. Of these, 428 (22.6%) patients reported frequent (⩾7) gout flares. The MSU and MSKF median scores were 6 and 9, respectively. For each five-point increase in MSU and MSKF score, the odds ratio of frequent gout flares increased 1.13-fold and 1.24-fold, respectively. The area under the curve (AUC) for the MSU and MSKF score was 0.635 [95% confidence interval (CI): 0.604-0.665] and 0.688 (95% CI: 0.659-0.718), respectively, (AUC difference 0.054, p value for AUC difference < 0.001).ConclusionThe MSU and MSKF scores were significantly associated with the number of gout flares in the previous year. The MSKF score outperformed the MSU score in terms of frequent gout flare discrimination.
| S-EPMC10981851 | biostudies-literature
Project description:ImportanceThe prevalence of gout has increased in recent decades. Several clinical studies have demonstrated an association between gout and coronary heart disease, but direct cardiovascular imaging of monosodium urate (MSU) deposits by using dual-energy computed tomography (DECT) has not been reported to date.ObjectiveTo compare coronary calcium score and cardiovascular MSU deposits detected by DECT in patients with gout and controls.Design, setting, and participantsThis prospective Health Insurance Portability and Accountability Act-compliant study included patients with gout and controls who presented to a rheumatologic clinic from January 1, 2017, to November 1, 2018. All consecutive patients underwent DECT to assess coronary calcium score and MSU deposits in aorta and coronary arteries. In addition, cadavers were assessed by DECT for cardiovascular MSU deposits and verified by polarizing microscope. Analysis began in January 2017.Main outcomes and measuresDetection rate of cardiovascular MSU deposits using DECT in patients with gout and control group patients without a previous history of gout or inflammatory rheumatic diseases.ResultsA total of 59 patients with gout (mean [SD] age, 59 [5.7] years; range, 47-89 years), 47 controls (mean [SD] age, 70 [10.4] years; range, 44-86 years), and 6 cadavers (mean [SD] age at death, 76 [17] years; range, 56-95 years) were analyzed. The frequency of cardiovascular MSU deposits was higher among patients with gout (51 [86.4%]) compared with controls (7 [14.9%]) (χ2 = 17.68, P < .001), as well as coronary MSU deposits among patients with gout (19 [32.2%]) vs controls (2 [4.3%]) (χ2 = 8.97, P = .003). Coronary calcium score was significantly higher among patients with gout (900 Agatston units [AU]; 95% CI, 589-1211) compared with controls (263 AU; 95% CI, 76-451; P = .001) and also significantly higher among 58 individuals with cardiovascular MSU deposits (950 AU; 95% CI, 639-1261) compared with 48 individuals without MSU deposits (217 AU; 95% CI, 37-397; P < .001). Among 6 cadavers, 3 showed cardiovascular MSU deposits, which were verified by polarizing light microscope.Conclusion and relevanceDual-energy computed tomography demonstrates cardiovascular MSU deposits, as confirmed by polarized light microscopy. Cardiovascular MSU deposits were detected by DECT significantly more often in patients with gout compared with controls and were associated with higher coronary calcium score. This new modality may be of importance in gout population being at risk from cardiovascular disease.
| S-EPMC6739730 | biostudies-literature
Project description:Optical diffraction tomography (ODT) enables imaging of unlabeled intracellular components by measuring the three-dimensional (3D) refractive index (RI). We aimed to detect intracellular monosodium urate (MSU) crystals in synovial leukocytes derived from gout patients using ODT. The 3D RI values of the synthetic MSU crystals, measured by ODT, ranged between 1.383 and 1.440. After adding synthetic MSU crystals to a macrophage, RI tomograms were reconstructed using ODT, and the reconstructed RI tomograms discerned intracellular and extracellular MSU crystals. We observed unlabeled synthetic MSU crystal entry into the cytoplasm of a macrophage through time-lapse imaging. Furthermore, using gout patient-derived synovial leukocytes, we successfully obtained RI tomogram images of intracellular MSU crystals. The 3D RI identification of MSU crystals was verified with birefringence through polarization-sensitive ODT measurements. Together, our results provide evidence that this novel ODT can identify birefringent MSU crystals in synovial leukocytes of patients with gout.
| S-EPMC8113554 | biostudies-literature
Project description:Gouty arthritis is characterized by the deposition of monosodium urate (MSU) within synovial joints and tissues due to increased urate concentrations. Here, we elucidated the role of the natural compound cichoric acid (CA) on the MSU crystal-stimulated inflammatory response. The THP-1-derived macrophages (THP-Ms) were pretreated with CA and then stimulated with MSU suspensions. The protein levels of p65 and IκBα, the activation of the NF-κB signaling pathway by measuring the expression of its downstream inflammatory cytokines, and the activity of NLRP3 inflammasome were measured by western blotting and ELISA. CA treatment markedly inhibited the degradation of IκBα and the activation of NF-κB signaling pathway and reduced the levels of its downstream inflammatory genes such as IL-1β, TNF-α, COX-2, and PGE2 in the MSU-stimulated THP-M cells. Therefore, we infer that CA effectively alleviated MSU-induced inflammation by suppressing the degradation of IκBα, thereby reducing the activation of the NF-κB signaling pathway and the NLRP3 inflammasome. These results suggest that CA could be a novel therapeutic strategy in averting acute episodes of gout.
| S-EPMC7808822 | biostudies-literature
Project description:OBJECTIVE:To estimate the prevalence and distribution of asymptomatic monosodium urate monohydrate (MSU) crystal deposition in sons of patients with gout. METHODS:Patients with gout were mailed an explanatory letter with an enclosed postage-paid study packet to mail to their son(s) age ?20 years old. Sons interested in participating returned a reply form and underwent telephone screening. Subsequently, they attended a study visit at which blood and urine samples were obtained and musculoskeletal ultrasonography was performed, with the sonographer blinded with regard to the subject's serum urate level. Images were assessed for double contour sign, intraarticular or intratendinous aggregates/tophi, effusion, and power Doppler signal. Logistic regression was used to examine associations. Adjusted odds ratios (ORadj ) and 95% confidence intervals (95% CIs) were calculated. RESULTS:One hundred thirty-one sons (mean age 43.8 years, mean body mass index 27.1 kg/m2 ) completed assessments. The serum urate level was ?6 mg/dl in 64.1%, and 29.8% had either a double contour sign or intraarticular aggregates/tophi in ?1 joint. All participants with MSU deposition had involvement of 1 or both first metatarsophalangeal joints. Intratendinous aggregates were present in 21.4% and were associated with intraarticular MSU crystal deposits (ORadj 2.96 [95% CI 1.17-7.49]). No participant with a serum urate level of ?5 mg/dl had MSU crystal deposition seen on ultrasonography, and 24.2% of those with serum urate levels between 5 and 6 mg/dl had ultrasonographic MSU deposition. MSU crystal deposition was associated with increasing serum urate levels (ORadj 1.61 [95% CI 1.10-2.36] for each increase of 1 mg/dl). CONCLUSION:Asymptomatic sons of patients with gout frequently have hyperuricemia and MSU crystal deposits. In this study MSU crystal deposits were present in participants with serum urate levels of ?5 mg/dl. Evaluation of subjects without a family history of gout is needed to determine whether the threshold for MSU crystal deposition is also lower in the general population.
| S-EPMC6220843 | biostudies-other
Project description:Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1? (IL-1?) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases ?-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1? in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.
| S-EPMC5527297 | biostudies-literature
Project description:As a prominent feature of gout, monosodium urate (MSU) crystal deposition can induce gout flare, yet its impact on blood immune in gout remission patients still remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) is used to compare the gene expression profiling of peripheral blood mononuclear cells (PBMCs) among intercritical gout remission patients, advanced gout remission patients and healthy volunteers. The increase of HLA-DQA1high classical monocytes, and their important role in immune inflammatory responses and osteoclast differentiation are discovered in advanced gout remission patients. Moreover, the differentiation level of CD8+T cells are found to elevate in advanced gout remission patients, which is further validated via flow cytometry. It is also observed that pathways related to bone metabolism and inflammatory responses are overactive in advanced gout remission patients. By analysis on intercellular communication network, immune-related cell-cell interactions among PBMCs are shown to enhance in both intercritical and advanced gout remission patients. The analyses on gene expression and LC-MS/MS together indicate the increased metabolic level of arachidonic acid in gout remission patients with MSU deposition at the intercritical and advanced stage. The study reveals distinctive blood immune characteristics in gout remission with MSU deposition, which provides more sights into its pathogenesis.
2023-06-01 | GSE217561 | GEO
Project description:BACKGROUND:Dual-energy CT (DECT) can acknowledge differences in tissue compositions and can colour-code tissues with specific features including monosodium urate (MSU) crystals. However, when evaluating gout patients, DECT frequently colour-codes material not truly representing MSU crystals and this might lead to misinterpretations. The characteristics of and variations in properties of colour-coded DECT lesions in gout patients have not yet been systematically investigated. The objective of this study was to evaluate the properties and locations of colour-coded DECT lesions in gout patients. METHODS:DECT of the hands, knees and feet were performed in patients with suspected gout using factory default gout settings, and colour-coded DECT lesions were registered. For each lesion, properties [mean density (mean of Hounsfield Units (HU) at 80?kV and Sn150kV), mean DECT ratio and size] and location were determined. Subgroup analysis was performed post hoc evaluating differences in locations of lesions when divided into definite MSU depositions and possibly other lesions. RESULTS:In total, 4033 lesions were registered in 27 patients (23 gout patients, 3918 lesions; 4 non-gout patients, 115 lesions). In gout patients, lesions had a median density of 160.6 HU and median size of 6 voxels, and DECT ratios showed an approximated normal distribution (mean 1.06, SD 0.10), but with a right heavy tail consistent with the presence of smaller amounts of high effective atomic number lesions (e.g. calcium-containing lesions). The most common locations of lesions were 1st metatarsophalangeal (MTP1), knee and midtarsal joints along with quadriceps and patella tendons. Subgroup analyses showed that definite MSU depositions (large volume, low DECT ratio, high density) had a similar distribution pattern, whereas possible calcium-containing material (high DECT ratio) and non-gout MSU-imitating lesions (properties as definite MSU depositions in non-gout patients) were primarily found in some larger joints (knee, midtarsal and talocrural) and tendons (Achilles and quadriceps). MTP1 joints and patella tendons showed only definite MSU depositions. CONCLUSION:Colour-coded DECT lesions in gout patients showed heterogeneity in properties and distribution. MTP1 joints and patella tendons exclusively showed definite MSU depositions. Hence, a sole focus on these regions in the evaluation of gout patients may improve the specificity of DECT scans.
| S-EPMC7488422 | biostudies-literature