Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis.

Published on Jul 12, 2020in Cell Proliferation5.753
· DOI :10.1111/CPR.12868
Hao Pan2
Estimated H-index: 2
(Guangzhou University of Chinese Medicine),
Yuqing Lin1
Estimated H-index: 1
(Guangzhou University of Chinese Medicine)
+ 9 AuthorsDongfeng Chen22
Estimated H-index: 22
(Guangzhou University of Chinese Medicine)
Sources
Abstract
OBJECTIVES Wedelolactone exhibits regulatory effects on some inflammatory diseases. However, the anti-inflammatory mechanism of wedelolactone has not been entirely unravelled. Therefore, the present study focuses on investigating the mechanism of wedelolactone on NLRP3 inflammasome in macrophages and its influence on MSU-induced inflammation. MATERIALS AND METHODS BMDM, J774A.1 and PMA-differentiated THP-1 macrophages were primed with LPS and then stimulated with ATP or nigericin or MSU crystal in the presence or absence of wedelolactone. The cell lysates and supernatants were collected to detect NLRP3 inflammasome components such as NLRP3, ASC and caspase 1, as well as pyroptosis and IL-1β production. In addition, the anti-inflammatory effects of wedelolactone on MSU-induced peritonitis and arthritis mice were also evaluated. RESULTS We found that wedelolactone broadly inhibited NLRP3 inflammasome activation and pyroptosis and IL-1β secretion. Wedelolactone also block ASC oligomerization and speck formation. The inhibitory effects of wedelolactone were abrogated by PKA inhibitor H89, which also attenuated wedelolactone-enhanced Ser/Thr phosphorylation of NLRP3 at PKA-specific sites. Importantly, wedelolactone could abate MSU-induced IL-1β production and neutrophils migration into peritoneal cavity, and reduced caspase 1 (p20) and IL-1β expression in the joint tissue of MSU-induced arthritis. CONCLUSION Our results indicate that wedelolactone promotes the Ser/Thr phosphorylation of NLRP3 to inhibit inflammasome activation and pyroptosis partly through potentiating PKA signalling, thus identifying its potential use for treating MSU-induced peritonitis and gouty arthritis.
Download
📖 Papers frequently viewed together
182 Citations
12 Citations
11 Authors (Chang-Yu Yan, ..., Rong-Rong He)
2 Citations
References42
Newest
#1Sarah Stewart (University of Auckland)H-Index: 3
#1Sarah Stewart (University of Auckland)H-Index: 10
Last. Philip Robinson (UQ: University of Queensland)H-Index: 78
view all 5 authors...
Colchicine is a widely used drug to treat inflammatory diseases. Due to its long historical use in medicine, controlled clinical trials have been small and there remains some caution with the use of this drug in patients with co-morbidities. The aim of the study is to systematically examine the side effect profile of colchicine in controlled clinical trials across all published indications. A systematic review was conducted in accordance with PRISMA methodology. The Cochrane Library, MEDLINE and...
33 CitationsSource
#1Xican Li (Guangzhou University of Chinese Medicine)H-Index: 19
#2Tingting Wang (Guangzhou University of Chinese Medicine)H-Index: 13
Last. Dongfeng Chen (Guangzhou University of Chinese Medicine)H-Index: 22
view all 8 authors...
Abstract The antioxidant properties of coumestans have been investigated previously using inappropriate methods, which has resulted in misleading and inaccurate mechanisms being reported to account for their antioxidant behavior. In this study, the phenolic coumestan wedelolactone increased the viability of OH -treated mesenchymal stem cells (MSCs) in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl assay. Mechanistic analysis in vitro suggested that wedelolactone could scavenge various radicals, inc...
20 CitationsSource
#1Mao-Mao Zhu (CPU: China Pharmaceutical University)H-Index: 2
#2Long Wang (CPU: China Pharmaceutical University)H-Index: 2
Last. Liang Feng (CPU: China Pharmaceutical University)H-Index: 8
view all 13 authors...
Abstract The acute kidney injury(AKI) caused by nephrotoxic drugs contributes to inflammation and oxidative injury in podocytes. Wedelolactone (WED), a natural compound, is found with activities as anti-inflammation, anti-oxidative, anti-free radical,and etc. In this present study, MPC-5 cells were exposed to the nephrotoxic drugs doxorubicin (DOX). The results showed that WED significantly increased the SOD activity, CAT and GSH-Px levels, while significantly decreased the MDA content and ROS l...
11 CitationsSource
#1Karen V. Swanson (UNC: University of North Carolina at Chapel Hill)H-Index: 15
#2Meng Deng (UNC: University of North Carolina at Chapel Hill)H-Index: 12
Last. Jenny P-Y TingH-Index: 9
view all 3 authors...
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflam...
717 CitationsSource
#1Ping Wang (Ha Tai: Xiamen University)H-Index: 11
#2Jing Geng (Ha Tai: Xiamen University)H-Index: 9
Last. Lanfen Chen (Ha Tai: Xiamen University)H-Index: 22
view all 20 authors...
Reactive oxygen species (ROS) production in phagocytes is a major defense mechanism against pathogens. However, the cellular self-protective mechanism against such potential damage from oxidative stress remains unclear. Here we show that the kinases Mst1 and Mst2 (Mst1/2) sense ROS and maintain cellular redox balance by modulating the stability of antioxidant transcription factor Nrf2. Site-specific ROS release recruits Mst1/2 from the cytosol to the phagosomal or mitochondrial membrane, with RO...
47 CitationsSource
#1Neng Wang (Guangzhou University of Chinese Medicine)H-Index: 4
#1Neng Wang (Guangzhou University of Chinese Medicine)H-Index: 22
Last. Zhiyu Wang (Guangzhou University of Chinese Medicine)H-Index: 24
view all 12 authors...
Chinese formulas have been paid increasing attention in cancer multidisciplinary therapy due to their multi-targets and multi-substances property. Here, we aim to investigate the anti-breast cancer and chemosensitizing function of Ai Du Qing (ADQ) formula made up of Hedyotis diffusa, Curcuma zedoaria (Christm.) Rosc., Astragalus membranaceus (Fisch.) Bunge and Glycyrrhiza uralensis Fisch. Our findings revealed that ADQ significantly inhibited cell proliferation in both parental and chemo-resista...
12 CitationsSource
#1Tao Gong (USTC: University of Science and Technology of China)H-Index: 10
#2Wei Jiang (USTC: University of Science and Technology of China)H-Index: 60
Last. Rongbin Zhou (USTC: University of Science and Technology of China)H-Index: 31
view all 3 authors...
Inflammasomes are cytosolic protein complexes composed of innate immune sensors, the adaptor protein ASC, and the cysteine protease caspase-1. In response to microbial infection or ‘danger signals’, inflammasomes play critical roles in host defense or contribute to the pathogenesis of various inflammatory diseases. Recent studies have provided abundant evidence for a vital role of phosphorylation in the regulation of inflammasome assembly and activation. This review integrates previous observati...
28 CitationsSource
#1Matthew Mangan (University of Bonn)H-Index: 11
Last. Eicke LatzH-Index: 100
view all 6 authors...
The inflammasome is a key integration point for innate immunity. As such, targeting this signalling hub has the potential to be useful in numerous autoimmune and metabolic disorders. In this article, Latz and colleagues discuss the progress that has been made towards targeting the inflammasome, highlighting the therapeutic potential of some of these compounds as well as caveats for their use.
434 CitationsSource
#1Hongbin He (USTC: University of Science and Technology of China)H-Index: 3
#2Hua Jiang (USTC: University of Science and Technology of China)H-Index: 5
Last. Rongbin Zhou (USTC: University of Science and Technology of China)H-Index: 31
view all 11 authors...
Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interactio...
167 CitationsSource
#1Haipeng Yin (SDU: Shandong University)H-Index: 4
#1Haipeng Yin (SDU: Shandong University)H-Index: 1
Last. Jun Peng (SDU: Shandong University)H-Index: 29
view all 12 authors...
Turmeric is traditionally used as a spice and coloring in foods. Curcumin is the primary active ingredient in the turmeric, and compelling evidence has shown that it has the ability to inhibit inflammation. However, the mechanism mediating its anti-inflammatory effects are not fully understood. We report that curcumin inhibited caspase-1 activation and IL-1β secretion through suppressing LPS priming and the inflammasome activation pathway in mouse bone marrow–derived macrophages. The inhibitory ...
66 CitationsSource
Cited By9
Newest
#1Bin Zhang (WHU: Wuhan University)
#2Feng Zheng (WHU: Wuhan University)H-Index: 2
Last. Zongze Zhang (WHU: Wuhan University)H-Index: 15
view all 12 authors...
BACKGROUND Cannabinoid receptor 2 (CB2), whose activities are upregulated during sepsis, may be related to the regulation of inflammatory programmed cell death called pyroptosis. The aim of this study is to investigate the role of CB2 activation in attenuation of inflammation through inhibiting pyroptosis in cecal ligation puncture (CLP)-induced sepsis andlipopolysaccharide (LPS) + ATP-stimulated macrophages. METHODS C57BL/6 mice were subjected to CLP procedure and treated with CB2 agonist HU308...
Source
COVID-19 pandemic has proven to be a dramatic challenge, introducing huge clinical differences that demand extensive investigations. Severe and critical patients may present coagulopathies and microthrombi, which results in varied complications, or acute respiratory distress syndrome that leads to fatality. Although the lung to be the major site of clinical manifestations, COVID-19 has shown extrapulmonary manifestations, especially on the heart and kidney, directly linked to worse disease outco...
Source
#1Rong Fan (Dalian Medical University)H-Index: 8
#2Jidong Sui (Dalian Medical University)H-Index: 4
Last. Zhenming Gao (Dalian Medical University)H-Index: 12
view all 5 authors...
Abstract null null Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure. Pyroptosis and ferroptosis are two newly recognized cell death, and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities, the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury again...
Source
Abstract null null The NLRP3 inflammasome holds a crucial role in innate immune responses. Pathogen- and danger-associated molecular patterns may initiate inflammasome activation and following inflammatory cytokine release. The inflammasome formation and its-associated activity are involved in various pathological conditions such as cardiovascular, central nervous system, metabolic, renal, inflammatory and autoimmune diseases. Although the mechanism behind NLRP3-mediated disorders have not been ...
Source
#1Ming-Ye Chen (JNU: Jinan University)H-Index: 3
#2Xun-jia Ye (JNU: Jinan University)H-Index: 2
Last. Dong-Yun Ouyang (JNU: Jinan University)H-Index: 22
view all 4 authors...
The NLRP3 inflammasome is a multi-molecular complex that acts as a molecular platform to mediate caspase-1 activation, leading to IL-1β/IL-18 maturation and release in cells stimulated by various pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). This inflammasome plays an important role in the innate immunity as its activation can further promote the occurrence of inflammation, enhance the ability of host to remove pathogens, and thus facilitate the ...
1 CitationsSource
#1Yanbei Tu (UM: University of Macau)H-Index: 4
#2Ying Yang (UM: University of Macau)
Last. Chengwei He (UM: University of Macau)H-Index: 33
view all 4 authors...
Abstract Naturally occurring coumestans are known as a collection of plant-derived polycyclic aromatic secondary metabolites which are characterized by the presence of an oxygen heterocyclic four-ring system comprising a coumarin moiety and a benzofuran moiety sharing a C=C bond. Recently, there is an increasing attention in excavating the medicinal potential of coumestans, particularly coumestrol, wedelolactone, psoralidin and glycyrol, in a variety of diseases. This review is a comprehensive i...
Source
#1Yuyi Chen (Nanjing Medical University)H-Index: 1
#2Qiudong Yang (Nanjing Medical University)H-Index: 1
Last. Hua Yuan (Nanjing Medical University)H-Index: 1
view all 10 authors...
OBJECTIVES NLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied. MATERIALS AND METHODS We used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3KO ) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/RosanTnG mouse to trace the changes of Lysm-Cre+ osteoclast p...
4 CitationsSource
#1Yufei LuoH-Index: 1
#2Bo-Jun XiongH-Index: 2
Last. Jian YangH-Index: 10
view all 7 authors...
Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in v...
3 CitationsSource
#1Yuqing Lin (Guangzhou University of Chinese Medicine)H-Index: 1
#2Tianyu Luo (Guangzhou University of Chinese Medicine)H-Index: 1
Last. Hao Pan (Guangzhou University of Chinese Medicine)H-Index: 1
view all 11 authors...
Gallic acid is an active phenolic acid widely distributed in plants, and there is compelling evidence to prove its anti-inflammatory effects. NLRP3 inflammasome dysregulation is closely linked to many inflammatory diseases. However, how gallic acid affects the NLRP3 inflammasome remains unclear. Therefore, in the present study, we investigated the mechanisms underlying the effects of gallic acid on the NLRP3 inflammasome and pyroptosis, as well as its effect on gouty arthritis in mice. The resul...
5 CitationsSource