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.

scholarly journals Icarisid I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

2020 ◽  
Author(s):  
Yuan Gao ◽  
Guang Xu ◽  
Li Ma ◽  
Wei Shi ◽  
Zhilei Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Bone Fractures ◽  
Reactive Oxygen ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Hepatocyte Apoptosis ◽  
Specific Stimulus ◽  
Nlrp3 Inflammasome Activation

Abstract Background Epimedii Folium(EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI. Methods Mouse were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo. Results Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mice model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation. Conclusions Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI.

scholarly journals Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

2020 ◽  
Author(s):  
Yuan Gao ◽  
Zhaofang Bai ◽  
Xiaohe Xiao ◽  
guang Xu ◽  
ming Niu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Bone Fractures ◽  
Reactive Oxygen ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Hepatocyte Apoptosis ◽  
Specific Stimulus ◽  
Nlrp3 Inflammasome Activation

Abstract Background: Epimedii Folium(EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI.Methods: Mouse were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo.Results: Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mice model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation.Conclusions: Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI.

scholarly journals The NLRP3 inflammasome mediates DSS-induced intestinal inflammation in Nod2 knockout mice

2019 ◽  
Vol 25 (2) ◽  
pp. 132-143 ◽  
Author(s):  
Benjamin Umiker ◽  
Hyun-Hee Lee ◽  
Julia Cope ◽  
Nadim J. Ajami ◽  
Jean-Philippe Laine ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Chronic Disorder ◽  
Molecule Inhibitor ◽  
Pathway Inhibition

Crohn’s disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2−/− mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1β secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1β secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling.

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