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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

Abstract

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.

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Fig. 1: PCTR1 improves the survival rate in the LPS-induced acute inflammatory mouse model.
Fig. 2: PCTR1 ameliorates lung, liver, and kidney morphological damage.
Fig. 3: PCTR1 reduces LPS-stimulated inflammation.
Fig. 4: PCTR1 ameliorates respiratory function, liver function, and kidney function.
Fig. 5: PCTR1 decreases LPS-stimulated serum LA and AA levels.
Fig. 6: PCTR1 regulates the key enzymes of LA metabolism.
Fig. 7: PCTR1 increases serum SOD and GPX4 levels and reduces serum PGE2 and ROS levels.
Fig. 8: Schematic mechanism of PCTR1 regulates LA metabolism by promoting FADS1/FASDS2/ELOV2 expression and inhibiting PLA2 expression.

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Acknowledgements

We thank Jian-Guang Wang, Qian Wang, and Hong-Xia Mei for their supports and advices in our experiments. We are grateful to Biotree Bio-technology Co., Ltd. (Shanghai, China) for providing helps in data analysis. This work was funded by the grants from the National Natural Science Foundation of China (No. 81571862, No. 81870065), Natural Science Foundation of Zhejiang Province (No. LQ20H150003, No. LY19H150002), and Wenzhou Municipal Science and Technology Bureau (no. Y20190087, no. Y20190118).

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Correspondence to Yu Hao or Fang Gao or Sheng-wei Jin.

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Liu, Yj., Li, H., Tian, Y. et al. 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. Lab Invest 100, 904–915 (2020). https://doi.org/10.1038/s41374-020-0412-9

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