Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages.
Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages.
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超微粉化棕榈酰乙醇酰胺可抑制培养的小鼠肺泡巨噬细胞中 NLRP3 炎症小体的表达和由 SARS-CoV-2 刺突蛋白激活的促炎症反应。
DOI：
10.3390/metabo11090592
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发表时间：
2021-09-02
期刊：
影响因子：
4.1
通讯作者：
Esposito G
中科院分区：
文献类型：
--
作者：
Del Re A;Corpetti C;Pesce M;Seguella L;Steardo L;Palenca I;Rurgo S;De Conno B;Sarnelli G;Esposito G
尽管棕榈酰乙醇胺（PEA）可能具有抗COVID-19的治疗潜力，但其发挥其有益活性的确切机制仍不清楚。PEA已被证明具有镇痛、抗过敏和抗炎活性。PEA的大部分抗炎特性来自其通过选择性激活PPARα受体拮抗核因子-κB（NF-κB）信号传导途径的能力。在该位点，PEA可以作用于参与炎症反应的几个基因的下游，包括细胞因子（TNF-α，IL-1β）和其他信号介质，如诱导型一氧化氮合酶（iNOS）和COX 2。为了阐明这一点，我们在暴露于SARS-CoV-2刺突糖蛋白（SP）的小鼠肺泡巨噬细胞原代培养物中，测试了超微化（um）-PEA单独使用和与特异性过氧化物酶体增殖物激活受体α（PPAR-α）拮抗剂MK 886共同使用时的抗炎和免疫调节活性。与溶剂组相比，SP激发导致促炎性标志物（TLR 4、p-p38 MAPK、NF-κB）显著浓度依赖性增加，并导致炎性小体依赖性炎症通路（NLRP 3、Caspase-1）显著上调，同时IL-6、IL-1β、TNF-α过度释放。我们还观察到一个显着的浓度依赖性增加血管紧张素转换酶-2（ACE-2）后SP的挑战。um-PEA浓度依赖性地减少所有分析的促炎标志物，促进ACE-2的平行下调。我们的数据首次表明，um-PEA通过PPAR-α显著抑制SP诱导的NLRP 3信号通路，概述了这种脂质对抗COVID-19的新作用机制。
Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1β) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1β, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in angiotensin-converting enzyme-2 (ACE-2) following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.
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作者：
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