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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


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.


  1. 1.

    Simpson BW, Trent MS. Pushing the envelope: LPS modifications and their consequences. Nat Rev Microbiol. 2019;17:403–16.

    CAS  Article  Google Scholar 

  2. 2.

    Bannerman DD, Goldblum SE. Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. Am J Physiol Lung Cell Mol Physiol. 2003;284:L899–914.

    CAS  Article  Google Scholar 

  3. 3.

    O’Neill CM, Minihane AM. The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults. Proc Nutr Soc. 2017;76:64–75.

    Article  Google Scholar 

  4. 4.

    Hishikawa D, Shindou H, Kobayashi S, Nakanishi H, Taguchi R, Shimizu T. Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity. Proc Natl Acad Sci U S A. 2008;105:2830–5.

    CAS  Article  Google Scholar 

  5. 5.

    Rinschen MM, Ivanisevic J, Giera M, Siuzdak G. Identification of bioactive metabolites using activity metabolomics. Nat Rev Mol Cell Biol. 2019;20:353–67.

    CAS  Article  Google Scholar 

  6. 6.

    Hao Y, Zheng H, Wang RH, Li H, Yang LL, Bhandari S, et al. Maresin1 alleviates metabolic dysfunction in septic mice: A (1)H NMR-based metabolomics analysis. Mediators Inflamm. 2019;2019:2309175.

    Article  Google Scholar 

  7. 7.

    Dalli J, Colas RA, Arnardottir H, Serhan CN. Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity. 2017;46:92–105.

    CAS  Article  Google Scholar 

  8. 8.

    Ramon S, Dalli J, Sanger JM, Winkler JW, Aursnes M, Tungen JE, et al. The protectin PCTR1 is produced by human M2 macrophages and enhances resolution of infectious inflammation. Am J Pathol. 2016;186:962–73.

    CAS  Article  Google Scholar 

  9. 9.

    Samuelsson B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J Biol Chem. 2012;287:10070–80.

    CAS  Article  Google Scholar 

  10. 10.

    Baillie JK, Digard P. Influenza-time to target the host? N Engl J Med. 2013;369:191–3.

    CAS  Article  Google Scholar 

  11. 11.

    Yang JX, Li M, Chen XO, Lian QQ, Wang Q, Gao F, et al. Lipoxin A4 ameliorates lipopolysaccharide-induced lung injury through stimulating epithelial proliferation, reducing epithelial cell apoptosis and inhibits epithelial-mesenchymal transition. Respir Res. 2019;20:192.

    Article  Google Scholar 

  12. 12.

    Zhang HW, Wang Q, Mei HX, Zheng SX, Ali AM, Wu QX, et al. RvD1 ameliorates LPS-induced acute lung injury via the suppression of neutrophil infiltration by reducing CXCL2 expression and release from resident alveolar macrophages. Int Immunopharmacol. 2019;76:105877.

    CAS  Article  Google Scholar 

  13. 13.

    Zhuo XJ, Hao Y, Cao F, Yan SF, Li H, Wang Q, et al. Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide-induced acute lung injury. Exp Mol Med. 2018;50:49.

    Article  Google Scholar 

  14. 14.

    El-Lakany MA, Fouda MA, El-Gowelli HM, El-Gowilly SM, El-Mas MM. Gonadal hormone receptors underlie the resistance of female rats to inflammatory and cardiovascular complications of endotoxemia. Eur J Pharmacol. 2018;823:41–48.

    CAS  Article  Google Scholar 

  15. 15.

    Dunn WB, Broadhurst D, Begley P, Zelena E, Francis-McIntyre S, Anderson N, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc. 2011;6:1060–83.

    CAS  Article  Google Scholar 

  16. 16.

    Lin X, Zhao L, Tang S, Zhou Q, Lin Q, Li X, et al. Metabolic effects of basic fibroblast growth factor in streptozotocin-induced diabetic rats: A (1)H NMR-based metabolomics investigation. Sci Rep. 2016;6:36474.

    CAS  Article  Google Scholar 

  17. 17.

    Kind T, Wohlgemuth G, Lee DY, Lu Y, Palazoglu M, Shahbaz S, et al. FiehnLib: mass spectral and retention index libraries for metabolomics based on quadrupole and time-of-flight gas chromatography/mass spectrometry. Anal Chem. 2009;81:10038–48.

    CAS  Article  Google Scholar 

  18. 18.

    Chong J, Wishart DS, Xia J. Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr Protoc Bioinformatics. 2019;68:e86.

    Article  Google Scholar 

  19. 19.

    Alhouayek M, Muccioli GG. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci. 2014;35:284–92.

    CAS  Article  Google Scholar 

  20. 20.

    Das UN. Polyunsaturated fatty acids and sepsis. Nutrition. 2019;65:39–43.

    Article  Google Scholar 

  21. 21.

    Castro LF, Tocher DR, Monroig O. Long-chain polyunsaturated fatty acid biosynthesis in chordates: insights into the evolution of Fads and Elovl gene repertoire. Prog Lipid Res. 2016;62:25–40.

    CAS  Article  Google Scholar 

  22. 22.

    Gu M, Li Y, Tang H, Zhang C, Li W, Zhang Y, et al. Endogenous omega (n)-3 fatty acids in Fat-1 mice attenuated depression-like behavior, imbalance between microglial M1 and M2 phenotypes, and dysfunction of neurotrophins induced by lipopolysaccharide administration. Nutrients. 2018;10:1351.

  23. 23.

    Rozenfeld RA, Liu X, DePlaen I, Hsueh W. Role of gut flora on intestinal group II phospholipase A2 activity and intestinal injury in shock. Am J Physiol Gastrointest Liver Physiol. 2001;281:G957–963.

    CAS  Article  Google Scholar 

  24. 24.

    Dieter P, Kolada A, Kamionka S, Schadow A, Kaszkin M. Lipopolysaccharide-induced release of arachidonic acid and prostaglandins in liver macrophages: regulation by Group IV cytosolic phospholipase A2, but not by Group V and Group IIA secretory phospholipase A2. Cell Signal. 2002;14:199–204.

    CAS  Article  Google Scholar 

  25. 25.

    Scott DL, White SP, Browning JL, Rosa JJ, Gelb MH, Sigler PB. Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate. Science. 1991;254:1007–10.

    CAS  Article  Google Scholar 

  26. 26.

    Gao Y, Zhang H, Luo L, Lin J, Li D, Zheng S, et al. Resolvin D1 improves the resolution of inflammation via activating NF-kappaB p50/p50-mediated cyclooxygenase-2 expression in acute respiratory distress syndrome. J Immunol. 2017;199:2043–54.

  27. 27.

    Das UN. n-3 fatty acids, γ-linolenic acid, and antioxidants in sepsis. Crit Care. 2013;17:312.

    Article  Google Scholar 

  28. 28.

    Das UN. Combination of aspirin with essential fatty acids is superior to aspirin alone to prevent or ameliorate sepsis or ARDS. Lipids Health Dis. 2016;15:206.

    Article  Google Scholar 

  29. 29.

    Dalli J, Colas RA, Quintana C, Barragan-Bradford D, Hurwitz S, Levy BD, et al. Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: correlations with survival and clinical outcomes. Crit Care Med. 2017;45:58–68.

    CAS  Article  Google Scholar 

  30. 30.

    Das UN. Is sepsis a pro-resolution deficiency disorder? Med Hypotheses. 2013;80:297–9.

    CAS  Article  Google Scholar 

  31. 31.

    Das UN. HLA-DR expression, cytokines and bioactive lipids in sepsis. Arch Med Sci: AMS. 2014;10:325–35.

    CAS  Article  Google Scholar 

  32. 32.

    Das UN. Circulating microparticles in septic shock and sepsis-related complications. Minerva Anestesiol. 2019;85:571–6.

    Article  Google Scholar 

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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).

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