RESUMO
C-type lectin receptors (CLRs) are a family of pattern recognition receptors, which detect a broad spectrum of ligands via small carbohydrate-recognition domains (CRDs). CLEC12A is an inhibitory CLR that recognizes crystalline structures such as monosodium urate crystals. CLEC12A also recognizes mycolic acid, a major component of mycobacterial cell walls, and suppresses host immune responses. Although CLEC12A could be a therapeutic target for mycobacterial infection, structural information on CLEC12A was not available. We report here the crystal structures of human CLEC12A (hCLEC12A) in ligand-free form and in complex with 50C1, its inhibitory antibody. 50C1 recognizes human-specific residues on the top face of hCLEC12A CRD. A comprehensive alanine scan demonstrated that the ligand-binding sites of mycolic acid and monosodium urate crystals may overlap with each other, suggesting that CLEC12A utilizes a common interface to recognize different types of ligands. Our results provide atomic insights into the blocking and ligand-recognition mechanisms of CLEC12A and leads to the design of CLR-specific inhibitors.
Assuntos
Lectinas Tipo C , Receptores Mitogênicos , Lectinas Tipo C/imunologia , Lectinas Tipo C/química , Lectinas Tipo C/metabolismo , Humanos , Receptores Mitogênicos/química , Receptores Mitogênicos/imunologia , Receptores Mitogênicos/metabolismo , Cristalografia por Raios X , Ligantes , Ligação Proteica , Sítios de Ligação , Modelos Moleculares , Ácido Úrico/química , Ácido Úrico/metabolismo , Ácido Úrico/imunologiaRESUMO
Monosodium urate (MSU) crystal deposition in joints can lead to the infiltration of neutrophils and macrophages, and their activation plays a critical role in the pathological progress of gout. However, the role of MSU crystal physicochemical properties in inducing cell death in neutrophil and macrophage is still unclear. In this study, MSU crystals of different sizes are synthesized to explore the role of pyroptosis in gout. It is demonstrated that MSU crystals induce size-dependent pyroptotic cell death in bone marrow-derived neutrophils (BMNs) and bone marrow-derived macrophages (BMDMs) by triggering NLRP3 inflammasome-dependent caspase-1 activation and subsequent formation of N-GSDMD. Furthermore, it is demonstrated that the size of MSU crystal also determines the formation of neutrophil extracellular traps (NETs) and aggregated neutrophil extracellular traps (aggNETs), which are promoted by the addition of interleukin-1ß (IL-1ß). Based on these mechanistic understandings, it is shown that N-GSDMD oligomerization inhibitor, dimethyl fumarate (DMF), inhibits MSU crystal-induced pyroptosis in BMNs and J774A.1 cells, and it further alleviates the acute inflammatory response in MSU crystals-induced gout mice model. This study elucidates that MSU crystal-induced pyroptosis in neutrophil and macrophage is critical for the pathological progress of gout, and provides a new therapeutic approach for the treatment of gout.
Assuntos
Gota , Macrófagos , Neutrófilos , Piroptose , Ácido Úrico , Gota/patologia , Gota/metabolismo , Animais , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Camundongos , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/metabolismoRESUMO
BACKGROUND: Gout is a chronic inflammatory diseases caused by monosodium urate crystal deposition. However, the role of interleukin (IL)-36 in gout has not dbeen elucidated. METHODS: We enrolled 75 subjects, including 20 healthy controls (HC), 30 patients with acute gout attack and 25 patients in remission. Baseline data were obtained through clinical interrogation and laboratory data were obtained through tests of blood samples. Serum levels of IL-36α were detected using enzyme-linked immunosorbent assay. Spearman correlation analysis was used to investigate the correlation of IL-36α with other parameters. The diagnostic value of IL-36α was demonstrated using a receiver operating characteristic curve. RESULTS: The serum IL-36α level of gout patients in acute attack and remission stage was significantly higher than that of HC. Serum IL-36α was positively correlated with alanine transaminase (ALT) and aspartate transaminase (AST). Serum amyloid A (SAA) levels positively correlated with C-reactive protein levels and erythrocyte sedimentation rates. Glutamyl transpeptidase levels positively correlated with AST and ALT levels. CONCLUSION: In conclusion, serum IL-36α levels were elevated in patients with gout and correlated with the clinical markers of inflammation. Our findings suggest that IL-36α may be a novel inflammatory indicator for gout.
Assuntos
Biomarcadores , Gota , Interleucina-1 , Humanos , Gota/sangue , Gota/diagnóstico , Masculino , Pessoa de Meia-Idade , Feminino , Interleucina-1/sangue , Biomarcadores/sangue , Adulto , Aspartato Aminotransferases/sangue , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Alanina Transaminase/sangue , Curva ROC , Idoso , Proteína Amiloide A Sérica/metabolismo , Sedimentação Sanguínea , Estudos de Casos e Controles , Ácido Úrico/sangue , Relevância ClínicaRESUMO
Monosodium urate (MSU) crystals, the etiological agent of gout, are formed in joints and periarticular tissues due to long-lasting hyperuricemia. Although MSU crystal-triggered NLRP3 inflammasome activation and interleukin 1ß (IL-1ß) release are known to have key roles in gouty arthritis, recent studies revealed that MSU crystal-induced necrosis also plays a critical role in this process. However, it remains unknown what forms of necrosis have been induced and whether combined cell death inhibitors can block such necrosis. Here, we showed that MSU crystal-induced necrosis in murine macrophages was not dependent on NLRP3 inflammasome activation, as neither genetic deletion nor pharmacological blockade of the NLRP3 pathway inhibited the necrosis. Although many cell death pathways (such as ferroptosis and pyroptosis) inhibitors or reactive oxygen species inhibitors did not have any suppressive effects, necroptosis pathway inhibitors GSK'872 (RIPK3 inhibitor), and GW806742X (MLKL inhibitor) dose-dependently inhibited MSU crystal-induced necrosis. Moreover, a triple combination of GSK'872, GW806742X, and IDN-6556 (pan-caspase inhibitor) displayed enhanced inhibition of the necrosis, which was further fortified by the addition of MCC950 (NLRP3 inhibitor), suggesting that multiple cell death pathways might have been triggered by MSU crystals. Baicalin, a previously identified inhibitor of NLRP3, inhibited MSU crystal-induced inflammasome activation and suppressed the necrosis in macrophages. Besides, baicalin gavage significantly ameliorated MSU crystal-induced peritonitis in mice. Altogether, our data indicate that MSU crystals induce NLRP3-independent necrosis, which can be inhibited by combined inhibitors for multiple signaling pathways, highlighting a new avenue for the treatment of gouty arthritis.
Assuntos
Artrite Gotosa , Gota , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Gota/tratamento farmacológico , Gota/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Necrose/induzido quimicamente , Necrose/tratamento farmacológico , Transdução de Sinais , Ácido ÚricoRESUMO
We investigated the effects of bactericidal/permeability-increasing protein (BPI) alone or in combination with hyaluronic acid (HA) in two animal models: collagen-induced arthritis (CIA) and crystal-induced inflammation. In CIA, mice were intraperitoneally injected with PBS, HA, or BPI plus or minus HA, twice a week for 2 months, and then euthanized to collect paw and blood. Arthritis was assessed in ankle joints by clinical and histological evaluation. Pathogenic crystals were intraperitoneally injected in mice plus or minus BPI, or with a composition of BPI and HA. After sacrifice, total and differential leukocyte counts were determined. Cytokine levels were measured in serum and peritoneal fluids. In CIA mice, BPI improved clinical and histological outcomes (histological scores ≥2-fold), and downregulated inflammatory mediators (47-93%). In crystal-induced inflammation, BPI reduced leukocyte infiltration (total count: ≥60%; polymorphonuclear cells: ≥36%) and inhibited cytokine production (35-74%). In both models, when mice were co-treated with BPI and HA, the improvement of all parameters was greater than that observed after administration of the two substances alone. Results show that BPI attenuates CIA and inflammation in mice, and this effect is enhanced by HA co-administration. Combined use of BPI and HA represents an interesting perspective for new potential treatments in arthritis.
Assuntos
Artrite Experimental , Camundongos , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Mediadores da Inflamação/metabolismo , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Ácido Hialurônico/metabolismo , PermeabilidadeRESUMO
BACKGROUND: There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS: Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1ß release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS: AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1ß levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1ß levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION: Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.
Assuntos
Dor Aguda , Artrite Gotosa , Gota , Camundongos , Masculino , Animais , Ácido Úrico , Hiperalgesia/tratamento farmacológico , Angiotensina II , Receptor Tipo 2 de Angiotensina , Peroxidase , Camundongos Endogâmicos C57BL , Gota/tratamento farmacológico , Gota/metabolismo , Artrite Gotosa/tratamento farmacológico , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Anti-Inflamatórios/uso terapêutico , Edema/tratamento farmacológico , Antioxidantes/uso terapêutico , Dor Aguda/tratamento farmacológico , RNA MensageiroRESUMO
Background and Objectives: Deposits of monosodium urate (MSU) crystals due to increased levels of uric acid (UA) have been associated with bone formation and erosion, mainly in patients with chronic gout. The synovial membrane (SM) comprises several types of cells, including mesenchymal stem cells (SM-MSCs); however, it is unknown whether UA and MSU induce osteogenesis through SM-MSCs. Materials and Methods: Cultures of SM were immunotyped with CD44, CD69, CD90, CD166, CD105, CD34, and CD45 to identify MSCs. CD90+ cells were isolated by immunomagnetic separation (MACS), colony-forming units (CFU) were identified, and the cells were exposed to UA (3, 6.8, and 9 mg/dL) and MSU crystals (1, 5, and 10 µg/mL) for 3 weeks, and cellular morphological changes were evaluated. IL-1ß and IL-6 were determined by ELISA, mineralization was assessed by alizarin red, and the expression of Runx2 was assessed by Western blot. Results: Cells derived from SM and after immunomagnetic separation were positive for CD90 (53 ± 8%) and CD105 (52 ± 18%) antigens, with 53 ± 5 CFU identified. Long-term exposure to SM-MSCs by UA and MSU crystals did not cause morphological damage or affect cell viability, nor were indicators of inflammation detected. Mineralization was observed at doses of 6.8 mg/dL UA and 5 µg/mL MSU crystals; however, the differences were not significant with respect to the control. The highest dose of MSU crystals (10 µg/mL) induced significant Runx2 expression with respect to the control (1.4 times greater) and SM-MSCs cultured in the osteogenic medium. Conclusions: MSU crystals may modulate osteogenic differentiation of SM-MSCs through an increase in Runx2.
Assuntos
Gota , Células-Tronco Mesenquimais , Humanos , Ácido Úrico/farmacologia , Osteogênese , Subunidade alfa 1 de Fator de Ligação ao Core , ProteínasRESUMO
Cluster of differentiation (CD) 38, a major enzyme for nicotinamide adenine dinucleotide (NAD+) degradation, plays a key role in inflammation. Meanwhile, intracellular NAD+ decline is also associated with inflammatory responses. However, whether CD38 activation is involved in gouty inflammation has not been elucidated. The present study aimed to clarify the role of CD38 in monosodium urate crystals (MSU)-triggered inflammatory responses. The results showed that MSU crystals increased the protein expression of CD38 in time- and concentration-dependent manner in THP-1 macrophages and mouse bone marrow-derived macrophages (BMDMs). Moreover, intracellular NAD+ levels were reduced by MSU crystals along with the increased IL-1ß release. However, CD38 inhibition by 78c elevated intracellular NAD+ levels and suppressed IL-1ß release in MSU crystals-treated THP-1 macrophages and BMDMs. Interestingly, CD38 inhibition without significant elevation of intracellular NAD+ also decreased IL-1ß release driven by MSU crystals in THP-1 macrophages. In conclusion, the present study revealed that MSU crystals could activate CD38 with the ensuing intracellular NAD+ decline to promote inflammatory responses in THP-1 macrophages and BMDMs, while CD38 inhibition could suppress MSU crystals-triggered inflammatory responses, indicating that CD38 is a potential therapeutic target for gout.
Assuntos
ADP-Ribosil Ciclase 1/genética , Interleucina-1beta/genética , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/genética , Ácido Úrico/farmacologia , ADP-Ribosil Ciclase 1/agonistas , ADP-Ribosil Ciclase 1/metabolismo , Animais , Cristalização , Feminino , Regulação da Expressão Gênica , Gota/etiologia , Gota/genética , Gota/metabolismo , Gota/patologia , Humanos , Hiperuricemia/etiologia , Hiperuricemia/genética , Hiperuricemia/metabolismo , Hiperuricemia/patologia , Inflamação , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , NAD/metabolismo , Cultura Primária de Células , Transdução de Sinais , Células THP-1RESUMO
Trehalose dibehenate (TDB), a ligand for the macrophage-inducible C-type lectin, has shown promise as an adjuvant for preventative vaccines and also as an anticancer agent in murine assays. The potential for TDB to affect the antitumor immune response of human myeloid cells, however, has not been studied. We investigated the effect of the adjuvants TDB and monosodium urate (MSU) crystals on the protumor or antitumor immune phenotype of human monocytes, macrophages and monocyte-derived dendritic cells (Mo-DCs). TDB treatment alone led to an inflammatory response in all three cell types, which was most pronounced when using human monocytes, with MSU augmenting this response. TDB also decreased cell surface markers associated with a protumorigenic phenotype, with MSU showing some ability to augment this response. Notably, a significant reduction in CD115 was observed for all antigen-presenting cells upon TDB or MSU + TDB treatment. The potential to increase the antigen-presenting capabilities of the myeloid cells was also observed upon treatment with TDB and MSU + TDB, as indicated by the upregulation of cell surface markers such as CD86 for all three cell types and a favorable ratio of interleukin (IL)-12p40 to IL-10 for monocytes stimulated with MSU + TDB. There was no significant production of IL-12p40 by Mo-DC; however, in a mixed lymphocyte assay, MSU + TDB costimulation of Mo-DC led to a significant increase in CD4+ T-cell numbers and in the IL-12p40-to-IL-10 ratio. Taken together, these findings show for the first time the potential of MSU + TDB costimulation to favor a tumor-suppressive phenotype in human-derived myeloid cells.
Assuntos
Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Trealose , Ácido Úrico , Animais , Humanos , Macrófagos/citologia , Camundongos , Monócitos/citologia , Neoplasias , Fenótipo , Trealose/farmacologia , Ácido Úrico/farmacologiaRESUMO
OBJECTIVE: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.
Assuntos
Gota/classificação , Hiperuricemia/classificação , Terminologia como Assunto , Consenso , HumanosRESUMO
Background and objectives: Turmeric has assisted in the control of inflammation and pain for decades and has been used in combination with other nutraceuticals to treat acute and chronic osteoarthritis pain. Recently, the effect of turmeric, turmeric extract, or curcuminoids on musculoskeletal pain, either by themselves or in conjunction with other substances, has been reported. The aim of this study was to develop and characterize turmeric nanoparticles (T-NPs) for various parameters, both in vitro and in vivo. Materials and Methods: The T-NPs were successfully synthesized and characterized using particle size analysis, solubility improvement, SEM, EDX, X-ray diffraction, and in vivo antigout activity in mice model. Results: The T-NPs were of about 46 nm in size with a positive zeta potential +29.55 ± 3.44 and low polydispersity index (PDI) (0.264). Furthermore, the diseased mice, with induced gout via monosodium urate crystals, were treated with 5, 10, and 20 ppm T-NPs, administered orally, and the anti-gout potential was observed through measurement of joint diameter and changes in biochemical parameters, including lipid profile, renal function test, and liver function tests which significantly reduced the levels of these biochemical parameters. Conclusions: Uric acid levels were significantly reduced after the treatment with T-NPs. indicating that T-NPs show superior potential against gout management. Thus, T-NPs can be developed as an efficient antigout agent with minimum toxicities.
Assuntos
Curcuma , Supressores da Gota/administração & dosagem , Gota/tratamento farmacológico , Nanopartículas/administração & dosagem , Fitoterapia , Extratos Vegetais/administração & dosagem , Animais , Antioxidantes/síntese química , Antioxidantes/farmacologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Curcuma/química , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Difusão Dinâmica da Luz , Gota/sangue , Gota/induzido quimicamente , Gota/patologia , Supressores da Gota/química , Testes de Função Renal , Testes de Função Hepática , Camundongos , Nanopartículas/química , Extratos Vegetais/química , Análise Espectral , Triglicerídeos/sangue , Ácido Úrico/sangue , Ácido Úrico/síntese química , Ácido Úrico/farmacologia , Difração de Raios XRESUMO
OBJECTIVES: To identify independent risk factors that differentiate gout from pseudogout in patients that present with crystal-induced acute arthritis. METHODS: This cross-sectional study was conducted at Siriraj Hospital (Bangkok, Thailand) during the 25 May 2014-28 November 2014 study period. Patients who presented with crystal-induced acute arthritis were eligible for inclusion. Diagnosis of gout or pseudogout was made by microscopic visualization and analysis of crystals in synovial fluid. Patients with other causes of acute arthritis were excluded. Patients diagnosed with gout were compared with patients diagnosed with pseudogout and factors with a p value less than 0.05 were included in logistic regression analysis. RESULTS: A total of 103 patients were included. Gout and pseudogout were established in 59 (56.7%) and 44 (42.3%) patients, respectively. Gout patients were younger than pseudogout patients (66.9 ± 14.5 vs. 78.9 ± 12.0 years; p = 0.0001); had higher BMI (22.9 ± 2.5 vs. 21.0 ± 2.5 kg/m2; p = 0.001); had history of recurrent arthritis (91.5 vs. 9.1%; p = 0.001); had higher prevalence of below-knee arthritis (66.1 vs. 31.8%; p = 0.001); had less periarticular soft tissue swelling (57.6 vs. 81.8%; p = 0.01); and had hyperuricemia (8.0 ± 2.5 vs. 5.6 ± 2.7; p = 0.001). In adjusted multivariate analysis, hyperuricemia during acute arthritis/gouty attack characterized gout (OR 2.08, 95% CI 1.2-3.6), while monoarticular attack (OR 4.12, 95% CI 1.3-13.0) and periarticular soft tissue swelling (OR 4.03, 95% CI 1.1-14.9) were indications for pseudogout. CONCLUSIONS: The independent risk factors were found to differentiate gout from pseudogout: Gout: hyperuricemia during gouty attack; Pseudogout: monoarticular attack and periarticular soft tissue swelling.
Assuntos
Artrite/complicações , Condrocalcinose/diagnóstico , Gota/diagnóstico , Hiperuricemia/complicações , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Condrocalcinose/complicações , Estudos Transversais , Feminino , Gota/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , TailândiaRESUMO
We investigated the anti-inflammatory and analgesic effects of quercetin in monosodium urate crystals (MSU)-induced gout arthritis, and the sensitivity of quercetin effects to naloxone, an opioid receptor antagonist. Mice were treated with quercetin, and mechanical hyperalgesia was assessed at 1-24 h after MSU injection. In vivo, leukocyte recruitment, cytokine levels, oxidative stress, NFκB activation, and gp91phox and inflammasome components (NLRP3, ASC, Pro-caspase-1, and Pro-IL-1ß) mRNA expression by qPCR were determined in the knee joints at 24 h after MSU injection. Inflammasome activation was determined, in vitro, in lipopolysaccharide-primed macrophages challenged with MSU. Quercetin inhibited MSU-induced mechanical hyperalgesia, leukocyte recruitment, TNFα and IL-1ß production, superoxide anion production, inflammasome activation, decrease of antioxidants levels, NFκB activation, and inflammasome components mRNA expression. Naloxone pre-treatment prevented all the inhibitory effects of quercetin over MSU-induced gout arthritis. These results demonstrate that quercetin exerts analgesic and anti-inflammatory effect in the MSU-induced arthritis in a naloxone-sensitive manner.
RESUMO
The aim of this study was to assess the frequency of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluids (SFs) aspirated from wrist and finger joints of patients with previously diagnosed joint diseases. We reviewed the results of SF analysis of 1593 samples and identified 126 patients with effusions in the small joints of the hands and wrists. We reported from patients' medical files data about sex, age, diagnosis, disease duration and the microscopic SF results. The prevalence of CPP crystals in SF was 85.71% in CPP-crystals arthritis (CPP-CA), 19.35% in rheumatoid arthritis (RA), 13.89% in osteoarthritis (OA) and 0% in psoriatic arthritis (PsA), spondyloarthritis (SpA), gout and miscellanea. The prevalence of MSU crystals in SF was 83.3% in gout, 10% in PsA, 2.8% in OA and 0% in RA, SpA, miscellanea and CPP-CA. Consistent with previously reported data concerning the big joints, microcrystals can be frequently found also in the small joints of patients with previous diagnosis. The finding underlines the importance of analyzing SF from the hand and wrist joints in the attempt to identify comorbidities associated with the presence of crystals and to develop targeted treatment strategies.
Assuntos
Pirofosfato de Cálcio/análise , Articulações dos Dedos/química , Artropatias/diagnóstico , Doenças Reumáticas/diagnóstico , Líquido Sinovial/química , Ácido Úrico/análise , Articulação do Punho/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Cristalização , Feminino , Humanos , Artropatias/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Doenças Reumáticas/metabolismoRESUMO
Monosodium urate (MSU) crystals, which are highly precipitated in the joint cartilage, increase the production of cartilage-degrading enzymes and pro-inflammatory mediators in cartilage, thereby leading to gouty inflammation and joint damage. In this study, we investigated the effect of MSU crystals on the viability of human articular chondrocytes and the mechanism of MSU crystal-induced chondrocyte death. MSU crystals significantly decreased the viability of primary chondrocytes in a time- and dose-dependent manner. DNA fragmentation was observed in a culture medium of MSU crystal-treated chondrocytes, but not in cell lysates. MSU crystals did not activate caspase-3, a marker of apoptosis, compared with actinomycin D and TNF-α-treated cells. MSU crystals did not directly affect the expression of endoplasmic reticulum (ER) stress markers at the mRNA and protein levels. However, MSU crystals significantly increased the LC3-II level in a time-dependent manner, indicating autophagy activation. Moreover, MSU crystal-induced autophagy and subsequent chondrocyte death were significantly inhibited by 3-methyladenine, a blocker of autophagosomes formation. MSU crystals activated autophagy via inhibition of phosporylation of the Akt/mTOR signaling pathway. These results demonstrate that MSU crystals may cause the death of chondrocytes through the activation of the autophagic process rather than apoptosis or ER stress.
Assuntos
Autofagia , Condrócitos/metabolismo , Cristais Líquidos/toxicidade , Ácido Úrico/química , Apoptose , Autofagia/efeitos dos fármacos , Autofagia/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Humanos , Piroptose , Transdução de Sinais/efeitos dos fármacos , Ácido Úrico/farmacologiaRESUMO
BACKGROUND: Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation. METHODS: Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein. RESULTS: Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1ß release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge. CONCLUSIONS: Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.
Assuntos
Acrilamidas , Gota , Histona Desacetilases , Macrófagos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilenodiaminas , Ácido Úrico , Animais , Ácido Úrico/toxicidade , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/deficiência , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Gota/metabolismo , Gota/patologia , Camundongos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Masculino , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Artrite Gotosa/patologia , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacosRESUMO
The self-limiting nature of the inflammatory flare is a feature of gout. The effects of neutrophil extracellular traps (NETs) on gout have remarkably attracted researchers' attention. Aggregated NETs promote the resolution of gouty inflammation by packing monosodium urate (MSU) crystals, degrading cytokines and chemokines, and blocking neutrophil recruitment and activation. Deficiency of NETs aggravates experimental gout. Thus, aggregated NETs are assumed to be a possible mechanism for the spontaneous resolution of gout. It is feasible to envisage therapeutic strategies for targeting NETosis (NET formation process) in gout. However, recent studies have demonstrated that levels of NETs are not associated with disease activity and inflammation in human gout. Moreover, the process of MSU crystal trapping is not affected in the absence of neutrophils. This review has concentrated on the mechanisms and associations between NETs and gout.
Assuntos
Armadilhas Extracelulares , Gota , Humanos , Ácido Úrico/farmacologia , Neutrófilos , Inflamação , PercepçãoRESUMO
Gout is a chronic disease caused by monosodium urate crystal deposition, typically affecting the big toe, midfoot, and ankle. As it rarely involves the sacroiliac joints, it could be easily misdiagnosed as spondylarthritis. Here, we report the case of a patient with a long history of gout with recurrent low back pain. Computed tomography of the sacroiliac joint suggested sacroiliac arthritis, puncture biopsy indicated gout granuloma, and polarized light microscopy confirmed monosodium urate crystal deposits.
Assuntos
Artrite Gotosa , Gota , Sacroileíte , Humanos , Sacroileíte/diagnóstico por imagem , Sacroileíte/tratamento farmacológico , Ácido Úrico , Gota/diagnóstico , Gota/diagnóstico por imagem , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/patologia , Dor nas Costas/diagnóstico , Dor nas Costas/etiologia , Artrite Gotosa/diagnóstico , Artrite Gotosa/diagnóstico por imagemRESUMO
Gout with associated AA amyloidosis is an unusual finding. This form of amyloid is associated with chronic inflammatory changes often associated with amyloid deposits in the urine, as well as tissue involvement, and organ enlargement in some cases. The large majority of cases in the literature to date refer to gout with AA amyloid within the kidney. However, this is not exclusive, with reports in the liver, gastrointestinal tract, adrenal glands rectum, skin, and subcutaneous fat. The pathophysiological association between these two disease processes is open to debate. The employment of specific anti-inflammatory treatments is believed to have an impact on reducing the incidence of AA amyloidosis in some gout cases-notably the use of colchicine in cases of clinically defined gout attacks. However, this is by no means a universal finding. Here we report on a cutaneous case of gout with AA amyloidosis in a 73-year-old man Included in this case study is a review of the other 16 cases reported within the literature in an attempt to clarify the associated pathophysiological process between these two diseases and the anti-inflammatory treatment regimens employed which may impact the occurrence of AA amyloidosis.
Assuntos
Amiloidose , Gota , Dermatopatias Genéticas , Masculino , Humanos , Idoso , Gota/complicações , Gota/diagnóstico , Gota/tratamento farmacológico , Amiloidose/complicações , Amiloidose/diagnósticoRESUMO
Synovial fluid analysis can provide a prompt and definite diagnosis of crystal-induced arthritis, the most common acute inflammatory arthritis and a cause of chronic arthritis that may mimic rheumatoid, psoriatic, or peripheral spondyloarthritis. In many patients the diagnosis of gout or calcium pyrophosphate arthritis cannot be made with certainty without synovial fluid analysis. Additional information from fluid analysis can assist the clinician in honing the differential diagnosis of non-crystalline arthritis.