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.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Simpson BW, Trent MS. Pushing the envelope: LPS modifications and their consequences. Nat Rev Microbiol. 2019;17:403–16.
Bannerman DD, Goldblum SE. Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. Am J Physiol Lung Cell Mol Physiol. 2003;284:L899–914.
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.
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.
Rinschen MM, Ivanisevic J, Giera M, Siuzdak G. Identification of bioactive metabolites using activity metabolomics. Nat Rev Mol Cell Biol. 2019;20:353–67.
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.
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.
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.
Samuelsson B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J Biol Chem. 2012;287:10070–80.
Baillie JK, Digard P. Influenza-time to target the host? N Engl J Med. 2013;369:191–3.
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.
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.
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.
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.
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.
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.
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.
Chong J, Wishart DS, Xia J. Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr Protoc Bioinformatics. 2019;68:e86.
Alhouayek M, Muccioli GG. COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci. 2014;35:284–92.
Das UN. Polyunsaturated fatty acids and sepsis. Nutrition. 2019;65:39–43.
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.
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.
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.
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.
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.
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.
Das UN. n-3 fatty acids, γ-linolenic acid, and antioxidants in sepsis. Crit Care. 2013;17:312.
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.
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.
Das UN. Is sepsis a pro-resolution deficiency disorder? Med Hypotheses. 2013;80:297–9.
Das UN. HLA-DR expression, cytokines and bioactive lipids in sepsis. Arch Med Sci: AMS. 2014;10:325–35.
Das UN. Circulating microparticles in septic shock and sepsis-related complications. Minerva Anestesiol. 2019;85:571–6.
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).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Changes of Lipopolysaccharide-Induced Acute Kidney and Liver Injuries in Rats Based on Metabolomics Analysis
Journal of Inflammation Research (2021)
The American Journal of Pathology (2021)