Epoxyeicosatrienoic acids inhibit the activation of NLRP3 inflammasome in murine macrophages.,Journal of Cellular Physiology

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Epoxyeicosatrienoic acids inhibit the activation of NLRP3 inflammasome in murine macrophages.
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2020-05-26 , DOI: 10.1002/jcp.29806
Xiao-Qin Luo _{1,

2,

3} , Jia-Xi Duan _{4,

5} , Hui-Hui Yang ₁ , Chen-Yu Zhang ₁ , Chen-Chen Sun ₁ , Xin-Xin Guan ₁ , Jian-Bing Xiong ₁ , Cheng Zu ₁ , Jia-Hao Tao ₁ , Yong Zhou ₁ , Cha-Xiang Guan ₁

Affiliation

Epoxyeicosatrienoic acids (EETs) derived from arachidonic acid exert anti‐inflammation effects. We have reported that blocking the degradation of EETs with a soluble epoxide hydrolase (sEH) inhibitor protects mice from lipopolysaccharide (LPS)‐induced acute lung injury (ALI). The underlying mechanisms remain essential questions. In this study, we investigated the effects of EETs on the activation of nucleotide‐binding domain leucine‐rich repeat‐containing receptor, pyrin domain‐containing‐3 (NLRP3) inflammasome in murine macrophages. In an LPS‐induced ALI murine model, we found that sEH inhibitor 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl), TPPU, profoundly attenuated the pathological injury and inhibited the activation of the NLRP3 inflammasome, characterized by the reduction of the protein expression of NLRP3, ASC, pro‐caspase‐1, interleukin precursor (pro‐IL‐1β), and IL‐1β p17 in the lungs of LPS‐treated mice. In vitro, primary peritoneal macrophages from C57BL/6 were primed with LPS and activated with exogenous adenosine triphosphate (ATP). TPPU treatment remarkably reduced the expression of NLRP3 inflammasome‐related molecules and blocked the activation of NLRP3 inflammasome. Importantly, four EETs (5,6‐EET, 8,9‐EET, 11,12‐EET, and 14,15‐EET) inhibited the activation of NLRP3 inflammasome induced by LPS + ATP or LPS + nigericin in macrophages in various degree. While the inhibitory effect of 5,6‐EET was the weakest. Mechanismly, EETs profoundly decreased the content of reactive oxygen species (ROS) and restored the calcium overload in macrophages receiving LPS + ATP stimulation. In conclusion, this study suggests that EETs inhibit the activation of the NLRP3 inflammasome by suppressing calcium overload and ROS production in macrophages, contributing to the therapeutic potency to ALI.

中文翻译：

环氧二十碳三烯酸抑制鼠巨噬细胞中NLRP3炎性小体的活化。

花生四烯酸衍生的环氧二十碳三烯酸（EET）具有抗炎作用。我们已经报道了用可溶性环氧化物水解酶（sEH）抑制剂阻止EET的降解可保护小鼠免于脂多糖（LPS）诱导的急性肺损伤（ALI）。潜在的机制仍然是基本问题。在这项研究中，我们研究了EET对鼠巨噬细胞中核苷酸结合结构域富含亮氨酸重复序列的受体，含吡喃结构域3（NLRP3）炎性小体的激活的影响。在LPS诱导的ALI鼠模型中，我们发现sEH抑制剂1-三氟甲氧基苯基-3-（1-丙酰哌啶-4-基）TPPU可以显着减轻病理损伤并抑制NLRP3炎性小体的活化，其特征是还原NLRP3，ASC，前胱天蛋白酶-1的蛋白表达 LPS处理的小鼠肺中的白介素前体（pro-IL-1β）和IL-1βp17。在体外，来自C57BL / 6的主要腹膜巨噬细胞用LPS灌注并用外源三磷酸腺苷（ATP）激活。TPPU处理显着降低了NLRP3炎性小体相关分子的表达，并阻断了NLRP3炎性小体的激活。重要的是，四种EET（5,6-EET，8,9-EET，11,12-EET和14,15-EET）在不同程度上抑制了巨噬细胞中LPS + ATP或LPS +尼日利亚菌素诱导的NLRP3炎性体的激活。。5,6-EET的抑制作用最弱。从机制上讲，EET可以显着降低活性氧物质（ROS）的含量并恢复接受LPS + ATP刺激的巨噬细胞的钙超载。结论，

更新日期：2020-05-26

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