PCTR1 ameliorates lipopolysaccharide-induced acute inflammation and multiple organ damage via regulation of linoleic acid metabolism by promoting FADS1/FASDS2/ELOV2 expression and reducing PLA2 expression
PCTR1 ameliorates lipopolysaccharide-induced acute inflammation and multiple organ damage via regulation of linoleic acid metabolism by promoting FADS1/FASDS2/ELOV2 expression and reducing PLA2 expression
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PCTR1 通过促进 FADS1/FASDS2/ELOV2 表达和减少 PLA2 表达来调节亚油酸代谢，改善脂多糖诱导的急性炎症和多器官损伤
DOI：
10.1038/s41374-020-0412-9
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发表时间：
2020-03-02
影响因子：
5
通讯作者：
Jin, Sheng-wei
中科院分区：
文献类型：
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作者：
Liu, Yong-jian;Li, Hui;Jin, Sheng-wei
革兰氏阴性细菌感染因其外膜成分脂多糖（LPS）而导致过度炎症反应和急性器官损伤或功能障碍。组织再生保护素结合物 1 (PCTR1) 是一种内源性脂质介质，在感染过程中发挥基本的抗炎和促消退作用。在本研究中，我们在 LPS 诱导的急性炎症小鼠模型中检查了 PCTR1 对全身炎症反应、有机形态损伤和功能障碍以及血清代谢生物标志物的特性。结果表明，PCTR1可减少血清炎症因子，改善肺、肝、肾的形态损伤和功能障碍，最终提高LPS诱导的小鼠急性炎症的存活率。此外，代谢组学分析和高效液相色谱-质谱分析表明，PCTR1 显着改变 LPS 刺激的血清亚油酸 (LA)、花生四烯酸 (AA) 和前列腺素 E2 (PGE2) 水平。此外，PCTR1上调LPS抑制的脂肪酸去饱和酶1（FADS1）、脂肪酸去饱和酶2（FADS2）和超长链脂肪酸延长酶2（ELOVL2）的表达，并下调LPS刺激的磷脂酶A2（PLA2）的表达，从而增加肝内AA含量。然而，PCTR1 的这些作用被脂氧素 A4 受体 (ALX) 拮抗剂 (BOC-2) 部分消除。综上所述，PCTR1通过激活ALX，通过上调FADS1、FADS2和ELOVL2的表达，促进LA向AA的转化，并通过下调PLA2的表达，抑制结合的AA向游离AA的转化，从而降低血清AA和PGE2的水平。
Gram-negative bacterial infection causes an excessive inflammatory response and acute organ damage or dysfunction due to its outer membrane component, lipopolysaccharide (LPS). Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenous lipid mediator, exerts fundamental anti-inflammation and pro-resolution during infection. In the present study, we examined the properties of PCTR1 on the systemic inflammatory response, organic morphological damage and dysfunction, and serum metabolic biomarkers in an LPS-induced acute inflammatory mouse model. The results show that PCTR1 reduced serum inflammatory factors and ameliorated morphological damage and dysfunction of the lung, liver, kidney, and ultimately improved the survival rate of LPS-induced acute inflammation in mice. In addition, metabolomics analysis and high performance liquid chromatography-mass spectrometry revealed that LPS-stimulated serum linoleic acid (LA), arachidonic acid (AA), and prostaglandin E2 (PGE2) levels were significantly altered by PCTR1. Moreover, PCTR1 upregulated LPS-inhibited fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2), and elongase of very long chain fatty acids 2 (ELOVL2) expression, and downregulated LPS-stimulated phospholipase A2 (PLA2) expression to increase the intrahepatic content of AA. However, these effects of PCTR1 were partially abrogated by a lipoxin A4 receptor (ALX) antagonist (BOC-2). In summary, via the activation of ALX, PCTR1 promotes the conversion of LA to AA through upregulation of FADS1, FADS2, and ELOVL2 expression, and inhibits the conversion of bound AA into free AA through downregulation of PLA2 expression to decrease the serum AA and PGE2 levels.