Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis.
Wedelolactone facilitates Ser/Thr phosphorylation of NLRP3 dependent on PKA signalling to block inflammasome activation and pyroptosis.
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DOI：
10.1111/cpr.12868
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发表时间：
2020-09
影响因子：
8.5
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Pan H;Lin Y;Dou J;Fu Z;Yao Y;Ye S;Zhang S;Wang N;Liu A;Li X;Zhang F;Chen D
Wedelolactone对某些炎症性疾病具有调节作用。然而，雷公藤内酯酮的抗炎机制尚未完全阐明。因此，本研究的重点是研究Wedelolactone对巨噬细胞中NLRP 3炎性小体的作用机制及其对MSU诱导的炎症的影响。用LPS引发BMDM、J774A.1和PMA分化的THP-1巨噬细胞，然后在存在或不存在wedelolactone的情况下用ATP或尼日利亚菌素或MSU晶体刺激。收集细胞裂解物和上清液以检测NLRP 3炎性体组分如NLRP 3、ASC和半胱天冬酶1，以及焦亡和IL-1β产生。此外，还评价了wedelolactone对MSU诱导的腹膜炎和关节炎小鼠的抗炎作用。我们发现，wedelolactone广泛抑制NLRP 3炎性小体活化和焦亡以及IL-1β分泌。Wedelolactone还阻断ASC寡聚化和斑点形成。PKA抑制剂H89消除了wedelolactone的抑制作用，也减弱了wedelolactone增强的NLRP 3在PKA特异性位点的Ser/Thr磷酸化。重要的是，wedelolactone可以减少MSU诱导的IL-1β的产生和中性粒细胞向腹腔的迁移，并减少MSU诱导的关节炎关节组织中caspase 1（p20）和IL-1β的表达。我们的研究结果表明，wedelolactone促进NLRP 3的Ser/Thr磷酸化，部分通过增强PKA信号传导来抑制炎性小体活化和焦亡，从而确定其用于治疗MSU诱导的腹膜炎和痛风性关节炎的潜在用途。Wedelolactone是传统草药墨旱莲的主要活性成分，对多种刺激引发的NLRP 3炎性小体激活具有广谱抑制作用。Wedelolactone通过增强PKA依赖性NLRP 3磷酸化抑制NLRP 3炎性小体组装、焦亡和IL-1β分泌。重要的是，在MSU诱导的腹膜炎和痛风性关节炎中，wedelolactone可以减轻NLRP 3相关炎症。
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. 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. 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. 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. Wedelolactone is a major active ingredient of the traditional medicinal herb eclipta, which demonstrates a broad‐spectrum inhibition effect on NLRP3 inflammasome activation triggered by multiple stimuli. Wedelolactone suppresses NLRP3 inflammasome assembly, pyroptosis and IL‐1β secretion through heightening PKA‐dependent NLRP3 phosphorylation. Importantly, wedelolactone could alleviate NLRP3‐related inflammation in MSU‐induced peritonitis and gouty arthritis.
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