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Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-{kappa}B/NLRP3 inflammasome circuit [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2020-11-10 , DOI: 10.1073/pnas.2000466117
Roger Flores-Costa 1, 2 , Marta Duran-Güell 1, 2 , Mireia Casulleras 1, 2 , Cristina López-Vicario 1, 2 , José Alcaraz-Quiles 1 , Alba Diaz 3 , Juan J. Lozano 4 , Esther Titos 1, 4, 5 , Katherine Hall 6 , Renee Sarno 6 , Jaime L. Masferrer 6 , Joan Clària 1, 2, 4, 5
Affiliation  

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3′,5′-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.



中文翻译:

刺激可溶性鸟苷酸环化酶通过VASP / NF- {kappa} B / NLRP3炎性体循环在肝脏中发挥抗炎作用[免疫学和炎症]

可溶性鸟苷酸环化酶(sGC)催化将鸟苷三磷酸转化为环状鸟苷3',5'-单磷酸,这是细胞信号传导和组织稳态的关键第二信使。最近证实,sGC刺激与实验性非酒精性脂肪性肝炎(NASH)小鼠的肝脏具有明显的抗炎作用。在这里,我们调查了肝中sGC刺激剂praliciguat(PRL)的抗炎作用的潜在机制。PRL的治疗性给药对胆碱缺乏的l-氨基酸定义的高脂饮食诱导的NASH的小鼠具有抗炎和抗纤维化的作用。PRL抗炎作用与较低的F4 / 80和CX3CR1阳性巨噬细胞浸入肝脏同时降低Ly6C有关-和更高的Ly6C-表达于外周循环单核细胞。PRL抗炎作用还与抑制肝细胞白介素(IL)-1β,NLPR3(NACHT,LRR和含PYD域的蛋白质3),ASC(与凋亡相关的斑点样蛋白质,含有caspase-recruitment结构域)有关)和活性裂解的caspase-1,它们是NLRP3炎性小体的组成部分。在用脂多糖加三磷酸腺苷的经典炎症小体模型攻击的库普弗细胞中,PRL抑制了启动(Il1bNlrp3的表达)并阻止成熟IL-1β的释放。从机理上讲,PRL诱导了蛋白激酶G(PKG)介导的VASP(血管扩张剂刺激的磷蛋白)Ser239残基的磷酸化,进而降低了核因子-κB(NF-κB)活性以及Il1bNlrp3基因转录。PRL还降低了独立于pannexin-1活性的裂解的caspase-1活性水平。这些数据表明,PRL sGC刺激通过与PKG / VASP /NF-κB/ NLRP3炎性体循环相关的机制在肝脏中发挥抗炎作用。

更新日期:2020-11-12
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