scholarly journals Epigallocatechin-3-Gallate Prevents Acute Gout by Suppressing NLRP3 Inflammasome Activation and Mitochondrial DNA Synthesis

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2138 ◽  
Author(s):  
Hye Eun Lee ◽  
Gabsik Yang ◽  
Youn Bum Park ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Nlrp3 Inflammasome ◽  
De Novo ◽  
Inflammasome Activation ◽  
Acute Gout ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Mitochondrial Dna Synthesis ◽  
Msu Crystals

Gout is a chronic inflammatory disease evoked by the deposition of monosodium urate (MSU) crystals in joint tissues. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the gout inflammatory symptoms induced by MSU crystals. We investigated whether epigallocatechin-3-gallate (EGCG) suppresses the activation of the NLRP3 inflammasome, thereby effectively preventing gouty inflammation. EGCG blocked MSU crystal-induced production of caspase-1(p10) and interleukin-1β in primary mouse macrophages, indicating its suppressive effect on the NLRP3 inflammasome. In an acute gout mouse model, oral administration of EGCG to mice effectively alleviated gout inflammatory symptoms in mouse foot tissue injected with MSU crystals. The in vivo suppressive effects of EGCG correlated well with the suppression of the NLRP3 inflammasome in mouse foot tissue. EGCG inhibited the de novo synthesis of mitochondrial DNA as well as the production of reactive oxygen species in primary mouse macrophages, contributing to the suppression of the NLRP3 inflammasome. These results show that EGCG suppresses the activation of the NLRP3 inflammasome in macrophages via the blockade of mitochondrial DNA synthesis, contributing to the prevention of gouty inflammation. The inhibitory effects of EGCG on the NLRP3 inflammasome make EGCG a promising therapeutic option for NLRP3-dependent diseases such as gout.

scholarly journals New mitochondrial DNA synthesis enables NLRP3 inflammasome activation

Nature ◽  
2018 ◽  
Vol 560 (7717) ◽  
pp. 198-203 ◽  
Author(s):  
Zhenyu Zhong ◽  
Shuang Liang ◽  
Elsa Sanchez-Lopez ◽  
Feng He ◽  
Shabnam Shalapour ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Mitochondrial Dna Synthesis

scholarly journals Author Correction: Mitochondrial DNA synthesis fuels NLRP3 inflammasome

Cell Research ◽  
2018 ◽  
Vol 28 (12) ◽  
pp. 1202-1202 ◽  
Author(s):  
Rebecca C. Coll ◽  
Caroline L. Holley ◽  
Kate Schroder
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Nlrp3 Inflammasome ◽  
Mitochondrial Dna Synthesis

Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in non-alcoholic fatty liver disease

2021 ◽  
Author(s):  
Lu Xu ◽  
Jingyang Zhou ◽  
Jinhui Che ◽  
Haihong Wang ◽  
Weizhong Yang ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Liver Disease ◽  
Fatty Liver ◽  
Dna Synthesis ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Inflammasome Activation ◽  
High Fat ◽  
Related Proteins ◽  
Mitochondrial Dna Synthesis

Nonalcoholic fatty liver disease (NAFLD) is typified by accumulating excess liver triacylglycerol, inflammation, and liver dysfunction. This study was aimed to investigate the role of mitochondrial DNA synthesis-induced activation of Absent in melanoma 2 (AIM2) inflammasome and pyroptosis in NAFLD. Mice were raised on a high-fat diet for 24 weeks to establish NAFLD models. F4/80 immunofluorescence was performed to reflect the inflammatory response in the liver of mice. Western blot, ELISA, and immunofluorescence were adopted to determine the expression of AIM2 inflammasome-related proteins and factors. EdU immunofluorescence was applied for the examination of mitochondrial DNA expression and flow cytometry for cell pyroptosis. Agarose gel electrophoresis was used to detect the integrity of extracted mouse mitochondrial DNA (mtDNA). The levels of AIM2 inflammasome-related proteins in the liver and the levels of IL-1β and IL-18 in serum were elevated in high-fat diet-induced NAFLD mice. AIM2 inflammasome activation and pyroptosis were triggered, and suppressed activation of AIM2 inflammasome alleviated the inflammation and pyroptosis in the liver of NAFLD mice. Mitochondria were severely damaged and mtDNA was synthesized after NAFLD modeling. Further, mtDNA treatment could promote palmitate (PA)-induced activation of AIM2 inflammasome and pyroptosis. Moreover, inhibition of IRF1 gene alleviated PA-induced AIM2 inflammasome activation and pyroptosis. In conclusion, mitochondrial DNA synthesis could enable AIM2 inflammasome activation and induce the hepatocyte pyroptosis, thereby exacerbating NAFLD.

scholarly journals Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

2020 ◽  
Vol 21 (13) ◽  
pp. 4733
Author(s):  
Shahzad Nawaz Syed ◽  
Andreas Weigert ◽  
Bernhard Brüne
Keyword(s):  
Nlrp3 Inflammasome ◽  
De Novo ◽  
Inflammasome Activation ◽  
Relative Contribution ◽  
Mouse Macrophages ◽  
Sphingosine Kinases ◽  
Transcriptional Induction ◽  
Human And Mouse ◽  
Inflammasome Activity

Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation.

scholarly journals Mitochondrial DNA synthesis fuels NLRP3 inflammasome

Cell Research ◽  
2018 ◽  
Vol 28 (11) ◽  
pp. 1046-1047 ◽  
Author(s):  
Rebecca C. Coll ◽  
Caroline L. Holley ◽  
Kate Schroder
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Nlrp3 Inflammasome ◽  
Mitochondrial Dna Synthesis

scholarly journals Loganin Alleviates Gout Inflammation by Suppressing NLRP3 Inflammasome Activation and Mitochondrial Damage

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1071
Author(s):  
Nuri Choi ◽  
Gabsik Yang ◽  
Joo Hyeon Jang ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Oral Administration ◽  
Nlrp3 Inflammasome ◽  
De Novo ◽  
Mitochondrial Damage ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Air Pouch ◽  
Nlrp3 Inflammasome Activation ◽  
Molecule Inhibitor ◽  
Msu Crystals

Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for a small-molecule inhibitor of the NLRP3 inflammasome for the prevention of gout inflammation. We found that loganin suppressed MSU crystals-induced caspase-1 (p20) and interleukin (IL)-1β production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks formation in mouse primary macrophages, showing its ability to inhibit the NLRP3 inflammasome. In an air pouch inflammation model, oral administration of loganin to mice prevented MSU crystals-induced production of mature IL-1β and IL-18 in air pouch exudates, resulting in decreased neutrophil recruitment. Furthermore, oral administration of loganin suppressed MSU crystals-induced gout inflammation in a mouse foot gout model, which was accompanied by the inhibition of the NLRP3 inflammasome. Loganin blocked de novo synthesis of mitochondrial DNA in air pouches and foot tissues injected with MSU crystals. Consistently, loganin prevented MSU crystals-induced mitochondrial damage in macrophages, as it increased mitochondrial membrane potential and decreased the amount of mitochondrial reactive oxygen species. These data demonstrate that loganin suppresses NLRP3 inflammasome activation by inhibiting mitochondrial stress. These results suggest a novel pharmacological strategy to prevent gout inflammation by blocking NLRP3 inflammasome activation and mitochondrial dysfunction.

scholarly journals Lower Temperatures Exacerbate NLRP3 Inflammasome Activation by Promoting Monosodium Urate Crystallization, Causing Gout

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1919
Author(s):  
Huijeong Ahn ◽  
Gilyoung Lee ◽  
Geun-Shik Lee
Keyword(s):  
Environmental Factor ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Optimal Temperature ◽  
Monosodium Urate ◽  
Nlrp3 Inflammasome Activation ◽  
Hyperthermia Therapy ◽  
Effects Of Temperature ◽  
Lower Temperature ◽  
Msu Crystals

Gout is a recurrent and chronic form of arthritis caused by the deposition of monosodium urate (MSU) crystals in the joints. Macrophages intake MSU crystals, the trigger for NLRP3 inflammasome activation, which leads to the release of interleukin (IL)-1β and results in the flaring of gout. The effects of temperature, an environmental factor for MSU crystallization, on IL-1β secretion have not been well studied. This study examined the effects of temperature on inflammasome activation. Specific triggers activated canonical inflammasomes (NLRP3, NLRC4, and AIM2) in murine macrophages at various temperatures (25, 33, 37, 39, and 42 °C). The maturation of IL-1β and caspase-1 was measured as an indicator for inflammasome activation. As expected, the optimal temperature of inflammasome activation was 37 °C. The MSU crystal-mediated activation of inflammasome increased at temperatures lower than 37 °C and decreased at higher temperatures. MSU crystals at lower temperatures enhanced IL-1β secretion via the NLRP3 inflammasome pathway. A lower temperature promoted the formation of MSU crystals without changing phagocytosis. Overall, lower temperatures form more MSU crystals and enhance NLRP3 inflammasome activation. In light of these findings, it is possible that hyperthermia therapy may reduce gout flaring.

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