scholarly journals Highlight Article: Phagocytosis of monosodium urate crystals by human synoviocytes induces inflammation

2019 ◽  
Vol 244 (5) ◽  
pp. 344-351 ◽  
Author(s):  
Yessica Zamudio-Cuevas ◽  
Javier Fernández-Torres ◽  
Gabriela Angélica Martínez-Nava ◽  
Karina Martínez-Flores ◽  
Adriana Ramírez Olvera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Gouty Arthritis ◽  
Hypoxia Inducible Factor ◽  
Polarized Light ◽  
Synovial Cells ◽  
Monosodium Urate ◽  
Tnf Α ◽  
Crystal Induced Arthritis ◽  
Msu Crystals

Synovial cells play a crucial part in gouty arthritis, with different features for the inflammation within the joint. However, there is no information about how the synoviocytes can mediate the activation of inflammation. We hypothesized that the process of monosodium urate (MSU) crystal uptake alters the inflammatory response of synoviocytes through regulation of unknown mechanisms. Synoviocytes were stimulated with MSU crystals, and the phagocytosis index (PhIx) was evaluated by counting of cells with MSU ingested using polarized light microscopy. Additionally, transmission electron microscopy and flow cytometry were performed. Secretion of cytokines was measured by a panel of immunoassays. Changes in gene expression of hypoxia-inducible factor-1 ( HIF1A), von Hippel-Lindau ( VHL), and vascular endothelial growth factor ( VEGF) were evaluated by quantitative real-time PCR (qRT-PCR). Protein levels were detected by ELISA. MSU crystals induced a time-dependent increase in PhIx and the formation of numerous secretory vesicles and cavities located in the cytoplasm. Culture supernatants of MSU-treated cells had high levels of the cytokines IL-1β, IL-6, IL-8, TNF-α, and MCP-1, and the growth factors NGF and HGF. The decrease in HIF1A gene expression was 0.58-fold, and overexpression of VHL and VEGF genes was 1.98- and 4-fold, respectively, in MSU-treated synoviocytes compared to untreated cells. Additionally, VEGF levels were increased. The identification of phagocytosis of MSU crystals triggering an inflammatory cellular state in synoviocytes suggests a possible mechanism of synovial activation in the pathogenesis of crystal-induced arthritis. Impact statement Gout is distinguished by an inflammatory process that is mediated by phagocytosis of monosodium urate (MSU) crystals in synoviocytes by regulation of unknown mechanisms. Here we suggest that the synovial cells play a crucial role in gouty arthritis by activating inflammation by MSU uptake and increasing the secretion of pro-inflammatory cytokines IL-1β, IL-6, IL-8, TNF-α, MCP-1, and the growth factors NGF and HGF. We discuss some co-existing features in synoviocytes, including anomalous morphologies of the cells, and microvesicle formation, dysregulation in VEGF gene expression. We provide evidence that phagocytosis of MSU crystals triggers an inflammatory cellular state in synoviocytes in the pathogenesis of crystal-induced arthritis.

Study on the Anti-Gout Activity of Chlorogenic Acid: Improvement on Hyperuricemia and Gouty Inflammation

2014 ◽  
Vol 42 (06) ◽  
pp. 1471-1483 ◽  
Author(s):  
Zhao-Qing Meng ◽  
Zhao-Hui Tang ◽  
Yun-Xia Yan ◽  
Chang-Run Guo ◽  
Liang Cao ◽  
...  
Keyword(s):  
Uric Acid ◽  
Chlorogenic Acid ◽  
Gouty Arthritis ◽  
Monosodium Urate ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Factor Α ◽  
Anti Inflammation ◽  
Necrosis Factor ◽  
Msu Crystals

Gout is a metabolic disorder associated with hyperuricemia resulting in the deposition of monosodium urate (MSU) crystals in joints and tissues. Lowering serum uric acid (Sur) levels and anti-inflammation are highly essential in treating gout. Chlorogenic acid (CA), as one of the most abundant polyphenols in the Chinese medicines, has been rarely reported to have an anti-gout effect. The model of potassium oxonate (PO)-induced hyperuricemia in mice and MSU crystal-induced inflammation in rats has been established in this study. The potential beneficial effects and mechanisms of CA on hyperuricemia and gouty arthritis were elucidated. The results demonstrated that CA significantly decreased the Sur level by inhibiting the xanthine oxidase (XOD) activity but not increasing the urinary uric acid (Uur) level. In addition, CA also exhibited the effect of suppressing paw swelling. Further investigation indicated that CA improved the symptoms of inflammation induced by MSU crystals by inhibiting the production of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The present study suggests that CA may have a considerable potential for development as an anti-gouty arthritis agent for clinical application.

scholarly journals Tempuyung Leaves (Sonchus arvensis) Ameliorates Monosodium Urate Crystal-Induced Gouty Arthritis in Rats through Anti-Inflammatory Effects

2020 ◽  
Vol 8 (A) ◽  
pp. 220-224
Author(s):  
Rachmat Hidayat ◽  
Muhammad Reagan ◽  
Lusia Hayati
Keyword(s):  
Synovial Fluid ◽  
Inflammatory Cytokines ◽  
Gouty Arthritis ◽  
Monosodium Urate ◽  
White Rats ◽  
Tnf Α ◽  
Sonchus Arvensis ◽  
Msu Crystals ◽  
Pro Inflammatory Cytokines

BACKGROUND: Gouty arthritis, a chronic inflammatory disease characterized by severe pain and swelling in one or more synovial joints, as a result from joint deposition of monosodium urate (MSU) crystals. Tempuyung (Sonchus arvensis) is a plant that has been extensively studied in the role of shedding kidney stones and diuretics. It is presumed that it also has great potential in shedding MSU crystals in the joints. AIM: This study focused on exploring the anti-inflammatory role of tempuyung extract (ET) on pro-inflammatory cytokines in gout arthritis white rats. METHODS: The extraction of tempuyung was performed to obtain ET. A total of 30 Wistar rats were randomly divided into the following six groups, each containing five rats: Normal control group, MSU group (negative control), MSU + colchicine group (Col; 0.28 mg/kg), and MSU + ET group (at dose of 25 mg/kg, 50 mg/kg, and 100 mg/kg). Gouty arthritis was induced with 50 ml of MSU solution (20 mg/ml), which was injected into the left ankle joint cavity on day 7. Synovial fluid was evacuated for the examination of Western blotting of tumor necrosis factor-α (TNF-α). A portion of synovial tissue was fixed in 4% paraformaldehyde buffer for histopathological examination. Interleukin (IL)-1β levels in the synovial fluid of the joints were examined by IL-1β rat enzyme-linked immunosorbent assay. Statistical analysis was performed with way ANOVA followed by post hoc. RESULTS: The histopathological image of the MSU model group showed a large number of inflammatory cells depicting an inflammatory reaction. This inflammation response decreased in the ET treatment group in dose-dependent manner. ET showed the effect of decreased pro-inflammatory cytokines expression in both IL-1β and TNF-α, as the dose increased. CONCLUSION: Tempuyung extract possessed an anti-gout arthritis effect in white rats induced by MSU, by reducing the inflammatory response in the synovial joint.

scholarly journals Cichoric Acid Ameliorates Monosodium Urate-Induced Inflammatory Response by Reducing NLRP3 Inflammasome Activation via Inhibition of NF-kB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qi Wang ◽  
Bingfeng Lin ◽  
Zhifeng Li ◽  
Jie Su ◽  
Yulin Feng
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Gouty Arthritis ◽  
Inflammasome Activation ◽  
Cichoric Acid ◽  
Monosodium Urate ◽  
Protein Levels ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α

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.

scholarly journals 724 Evaluation of an anti-human IL-1β antibody in monosodium urate crystals-induced peritonitis model in hIL-1β HuGEMM™ mice

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A753-A753
Author(s):  
Xiaoyu An ◽  
Kaixia Lian ◽  
Jia Zheng ◽  
Fei Jian ◽  
Henry Li ◽  
...  
Keyword(s):  
Treatment Group ◽  
Murine Model ◽  
Gouty Arthritis ◽  
Chronic Inflammatory Disease ◽  
Vehicle Group ◽  
Inflammasome Activation ◽  
Monosodium Urate ◽  
Vehicle Treatment ◽  
Peritonitis Model ◽  
Msu Crystals

BackgroundGout is a chronic inflammatory disease featuring the deposition of monosodium urate (MSU) crystals in the synovial fluid of patients, followed by NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation and bioactive IL-1β release, which recruits neutrophils to the local inflammation sites. Blocking IL-1β function is becoming a a potent therapeutic approach for gout and gouty arthritis. Conventional MSU-induced peritonitis in C57BL/6 mice provides a simple and rapid evaluation of therapeutics targeting inflammasome activation. However, this murine model has limitations when it comes to the evaluation of human-specific antibodies, for example, anti-human IL-1β (anti-hIL-1β) monoclonal antibodies (mAb). Thus, a murine model to assess the efficacy of anti-hIL-1β mAb is needed. We have developed a hIL-1β knock-in mouse model (hIL-1β HuGEMM™), which is able to facilitate the pre-clinical evaluation of drugs targeting specific human biological molecules especially when mouse ortholog is not available. Therefore, an MSU crystals induced peritonitis model using hIL-1β HuGEMM™ mice provides a robust model to evaluate therapies targeting hIL-1β.MethodsMSU crystals were injected intraperitoneally into human IL-1β (hIL-1β) knock-in mice, where the coding sequence of mouse IL-1β was replaced by hIL-1β. Prior to MSU crystal administration, mice received treatment of either vehicle or anti-hIL-1β antibody. Six hours facilitate post MSU crystal injection, serum and lavage flushed with PBS were collected. Subsequently, cytokine protein levels in the serum were determined by MSD, and the population of polymorphonuclear leukocytes (PMNs) (live CD11b+ Ly-6GHi cells) in the lavage was analysed by flow cytometry.ResultsThe vehicle treatment group showed a dramatic increase in hIL-1β secretion and PMN leukocytes, in comparison to the group that did not receive MSU, which suggests a successful induction of acute inflammatory response in the peritoneal cavity. In contrast, mice that received a single administration of anti-hIL-1β antibody 24 hours prior to MSU injection exhibited a significantly lower level of hIL-1β when compared to the vehicle treatment group, which implies that the anti-hIL-1β mAb efficaciously neutralized hIL-1β secretion. In addition, TNF-α and IL-6, two further cytokines downstream of IL-1β, were significantly reduced in the anti-hIL-1β mAb treatment group. However, the PMN leukocyte infiltration in the anti-hIL-1β mAb treatment group did not change in comparison to the vehicle group.ConclusionsIn this study, an MSU crystals-induced peritonitis model was successfully established in hIL-1β HuGEMM mice, which has the potential to evaluate immune therapeutics with anti-hIL-1β blockades.

scholarly journals Hyperuricemia and Gout – Ins and Out

2020 ◽  
Vol 15 (2) ◽  
pp. 227-234
Author(s):  
Md Abdur Razzak ◽  
Quazi Audry Arafat Rahman ◽  
Fahtiha Nasreen
Keyword(s):  
Gouty Arthritis ◽  
Polarized Light ◽  
Acute Gout ◽  
Women Patients ◽  
Monosodium Urate ◽  
Tophaceous Gout ◽  
First Metatarsal ◽  
Birefringent Crystals ◽  
Inflammatory Drugs ◽  
Urate Crystals

Gout is a condition characterized by the deposition of monosodium urate crystals in the joints or soft tissue. The four phases of gout include asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout and chronic tophaceous gout. The peak incidence occurs in patients 30 to 50 years old, and the condition is much more common in men than in women. Patients with asymptomatic hyperuricemia do not require treatment, but efforts should be made to lower their urate levels by encouraging them to make changes in diet or lifestyle. Acute gout most commonly affects the first metatarsal joint of the foot, but other joints are also commonly involved. Definitive diagnosis requires joint aspiration with demonstration of birefringent crystals in the synovial fluid under a polarized light microscope. Treatment includes nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids and analgesics. In patients without complications, NSAID therapy is preferred. JAFMC Bangladesh. Vol 15, No 2 (December) 2019: 227-234

Persistence of Crystals in Stored Synovial Fluid Samples

2020 ◽  
Vol 47 (9) ◽  
pp. 1416-1423
Author(s):  
Sonia Pastor ◽  
José-Antonio Bernal ◽  
Rocío Caño ◽  
Silvia Gómez-Sabater ◽  
Fernando Borras ◽  
...  
Keyword(s):  
Synovial Fluid ◽  
Light Microscopy ◽  
Room Temperature ◽  
Polarized Light ◽  
Calcium Pyrophosphate ◽  
Polarized Light Microscopy ◽  
Tetraacetic Acid ◽  
Monosodium Urate ◽  
Prospective Longitudinal ◽  
Msu Crystals

Objective.Lack of access to polarized light microscopy is often cited as an argument to justify the clinical diagnosis of crystal-related arthritis. We assessed the influence of time since sampling and preservation methods on crystal identification in synovial fluid (SF) samples under polarized light microscopy.Methods.This was a prospective, longitudinal, observational factorial study, analyzing 30 SF samples: 12 with monosodium urate (MSU) crystals and 18 with calcium pyrophosphate (CPP) crystals. Each SF sample was divided into 4 subsamples (120 subsamples in total). Two were stored in each type of preserving agent, heparin or ethylenediamine tetraacetic acid (EDTA), at room temperature or at 4°C. Samples were analyzed the following day (T1), at 3 days (T2), and at 7 days (T3) by simple polarized light microscopy, and the presence of crystals was recorded.Results.The identification of crystals in the MSU group was similar between groups, with crystals observed in 11/12 (91.7%) room temperature samples and in 12/12 (100%) refrigerated samples at T3. Identification of CPP crystals tended to decrease in all conditions, especially when preserved with EDTA at room temperature [12/18 (66.7%) at T3], while less reduction was seen in refrigerated heparin-containing tubes.Conclusion.Preserving samples with heparin in refrigerated conditions allows delayed microscopic examination for crystals. Avoiding crystal-proven diagnosis because of the immediate unavailability of microscopy no longer appears justified.

scholarly journals Effects of Modified Simiao Decoction on IL-1βand TNFαSecretion in Monocytic THP-1 Cells with Monosodium Urate Crystals-Induced Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ya-Fei Liu ◽  
Sheng-Hao Tu ◽  
Zhe Chen ◽  
Yu Wang ◽  
Yong-Hong Hu ◽  
...  
Keyword(s):  
Gouty Arthritis ◽  
Underlying Mechanism ◽  
Monosodium Urate ◽  
Future Studies ◽  
Treatment Groups ◽  
Chinese Herbal Formula ◽  
Chinese Herbal ◽  
Control Serum ◽  
Msu Crystals ◽  
Urate Crystals

Simiao pill, a Chinese herbal formula containing four herbs, has been used in the treatment of gouty arthritis for many years. The aim of this study was to explore the effects of modified Simiao decoction (MSD) on IL-1βand TNFαsecretion in monocytic THP-1 cells with monosodium urate (MSU) crystals-induced inflammation. The MSU crystals-induced inflammation model in THP-1 cells was successfully established by the stimulation of phorbol 12-myristate 13-acetate (PMA) and MSU crystals. Then, the MSD-derived serum or control serum extracted from rat was administered to different treatment groups. The morphology of MSU crystals and THP-1 cells was observed. IL-1βand TNFαprotein expression in supernatant of THP-1 cells were determined by ELISA. Our data demonstrated that MSU crystals induced time-dependent increase of IL-1βand TNFα. Moreover, MSD significantly decreased IL-1βrelease in THP-1 cells with MSU crystals-induced inflammation. These results suggest that MSD is promising in the treatment of MSU crystals-induced inflammation in THP-1 cells. MSD may act as an anti-IL-1 agent in treating gout. The underlying mechanism may be related to NALP3 inflammasome which needs to be validated in future studies.

Effects of Extracts from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on MSU Crystal-Induced Rats Gouty Arthritis

2009 ◽  
Vol 37 (04) ◽  
pp. 669-683 ◽  
Author(s):  
Ying Ma ◽  
Lan-Lan Zhou ◽  
Hai-Yan Yan ◽  
Mei Liu
Keyword(s):  
Immune Responses ◽  
Synovial Tissue ◽  
Gouty Arthritis ◽  
Rt Pcr ◽  
Traditional Herbal Medicine ◽  
Tnf Α ◽  
Antiinflammatory Effects ◽  
Paederia Scandens ◽  
Joint Volume ◽  
Msu Crystals

The effects of extract of Paederia scandens (LOUR.) MERRILL (Rubiaceae) (EPS), a Chinese traditional herbal medicine, on inflammatory and immune responses and their mechanisms in MSU crystals-induced (GA) rats were studied. GA rats were established. Ankle joint volume of rats was measured by volume meter; the level of TNF-α and IL-1β was determined by radioimmunoassay. mRNA expressions of TNF-α and IL-1β in synovial tissue of GA rats were analyzed by RT-PCR, and the expression of NF-κB was detected by immunohistochemistry. The administration of EPS (2.25, 4.5 g/kg, ig 9 days) inhibited the inflammatory response in GA rats. The mRNA expressions of TNF-α and IL-1β were also significantly suppressed in synovial tissue. In addition, EPS (2.25, 4.5 g/kg, ig 9 days) inhibited the expression of TNF-α and IL-1β and the biological activity of NF-κB. These results suggested that EPS possesses antiinflammatory effects by modulating pro-inflammatory mediators' production in synovial tissue and inactivating NF-κB pathway transmembrane signal transduction which plays a crucial role in the pathogenesis of this disease.

scholarly journals MiR-3146 Induces Neutrophil Extracellular Traps to Aggravate Acute Gouty Arthritis

2021 ◽  
Author(s):  
Lizhen Shan ◽  
Di Yang ◽  
Fabo Feng ◽  
Danjie Zhu ◽  
Xiaolin Li
Keyword(s):  
Potential Role ◽  
Gouty Arthritis ◽  
Neutrophil Extracellular Traps ◽  
Sirtuin 1 ◽  
Luciferase Reporter ◽  
Ros Production ◽  
Monosodium Urate ◽  
Acute Gouty Arthritis ◽  
Extracellular Traps ◽  
Msu Crystals

Abstract MiR-3146 plays an important role in the formation of neutrophil extracellular traps (NETs) during the pathogenesis of acute gouty arthritis (AGA).The aim of our study was to explore the underlying role and molecular mechanism of miR-3146 in the formation of neutrophil extracellular traps (NETs) during the pathogenesis of acute gouty arthritis (AGA). The expression of miR-3146 and sirtuin 1 (SIRT1) was determined by real-time PCR and western blot. The luciferase reporter assay was performed to identify the targeting relationship between miR-3146 and SIRT1. Reactive oxygen species (ROS) production was detected by fluorescent staining. NETs formation was demonstrated via immunofluorescence staining and ELISA method. AGA model was induced in rats to verify the effects of miR-3146 inhibition on histopathological changes and NETs. Here, we found miR-3146 expression was dramatically increased in neutrophils of patients with AGA, presenting higher levels of NETs. Monosodium urate (MSU) crystals significantly increased miR-3146 expression and ROS production in neutrophils. The NETs process was also triggered by MSU crystals. Furthermore, we verified the interaction between miR-3146 and SIRT1. Additionally, antagomir-3146-based therapy effectively inhibited the formation of NETs in rats with AGA. MiR-3146-mediated NETs formation may play a potential role in the pathogenesis of AGA.

Altered distribution and enhanced osteoclastogenesis of mucosal-associated invariant T cells in gouty arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (8) ◽  
pp. 2124-2134
Author(s):  
Young-Nan Cho ◽  
Hae-Seong Jeong ◽  
Ki-Jeong Park ◽  
Hyung-Seok Kim ◽  
Eun-Hee Kim ◽  
...  
Keyword(s):  
Cell Activation ◽  
Mononuclear Cells ◽  
Gouty Arthritis ◽  
Bone Destruction ◽  
Peripheral Blood Mononuclear ◽  
Mait Cells ◽  
Tnf Α ◽  
Mait Cell ◽  
Msu Crystals

Abstract Objective This study was designed to investigate the role of mucosal-associated invariant T (MAIT) cells in gouty arthritis (GA) and their effects on osteoclastogenesis. Methods Patients with GA (n = 61), subjects with hyperuricaemia (n = 11) and healthy controls (n = 30) were enrolled in this study. MAIT cells, cytokines, CD69, programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells in the presence of M-CSF and RANK ligand. Results Circulating MAIT cell levels were significantly reduced in GA patients. However, their capacities for IFN-γ, IL-17 and TNF-α production were preserved. Expression levels of CD69, PD-1 and LAG-3 in MAIT cells were found to be elevated in GA patients. In particular, CD69 expression in circulating MAIT cells was increased by stimulation with MSU crystals, suggesting that deposition of MSU crystals might contribute to MAIT cell activation. Interestingly, MAIT cells were found to be accumulated in synovial fluid and infiltrated into gouty tophus tissues within joints. Furthermore, activated MAIT cells secreted pro-resorptive cytokines (i.e. IL-6, IL-17 and TNF-α) and facilitated osteoclastogenesis. Conclusion This study demonstrates that circulating MAIT cells are activated and numerically deficient in GA patients. In addition, MAIT cells have the potential to migrate to inflamed tissues and induce osteoclastogenesis. These findings provide an important role of MAIT cells in the pathogenesis of inflammation and bone destruction in GA patients.

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