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TLR-2-mediated metabolic reprogramming participates in polyene phosphatidylcholine-mediated inhibition of M1 macrophage polarization

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Abstract

This study aimed to investigate whether the classic hepatoprotective drug polyene phosphatidylcholine (PPC) regulates macrophage polarization and explores the potential role of TLR-2 in this process. In RAW264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) stimulated by lipopolysaccharide (LPS), PPC significantly inhibited the production of IL-6, TNF-α, and the mRNA expression of M1-type macrophage markers. Consistently, PPC reduced the mRNA expression of several key enzymes in the pathways of glycolysis and lipid synthesis while increasing the expression of key enzymes associated with lipid oxidation. Moreover, blocking the glycolytic pathway using 2-deoxy-d-glucose (2-DG) significantly enhanced the anti-inflammatory effect of PPC. However, inhibition of lipid oxidation using GW9662 (an inhibitor of PPAR-γ) and GW6471 (an inhibitor of PPAR-α) abolished the anti-inflammatory effect of PPC. Interestingly, TLR-2 expression in macrophages was significantly downregulated after exposure to PPC. Moreover, pre-activation of TLR-2 hampered the anti-inflammatory effect of PPC. In addition, PPC did not inhibit the secretion of IL-6 and TNF-α in TLR-2−/− BMDMs that were activated by LPS. This was consistent with the increased expression of M1 markers and glycolytic and lipid synthesis enzymes but decreased lipid oxidation-related enzymes. These results showed that PPC inhibits the differentiation of M1-type macrophages, which was most likely related to TLR-2-mediated metabolic reprogramming.

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References

  1. Feito MJ, Diez-Orejas R, Cicuendez M, Casarrubios L, Rojo JM, Portoles MT. Characterization of M1 and M2 polarization phenotypes in peritoneal macrophages after treatment with graphene oxide nanosheets. Colloids Surf B: Biointerfaces. 2019;176:96–105.

    Article  CAS  PubMed  Google Scholar 

  2. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huang H, Fletcher A, Niu Y, Wang TT, Yu L. Characterization of lipopolysaccharide-stimulated cytokine expression in macrophages and monocytes. Inflamm Res. 2012;61:1329–38.

    Article  CAS  PubMed  Google Scholar 

  4. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011;12:231–8.

    Article  CAS  PubMed  Google Scholar 

  6. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.

    Article  CAS  PubMed  Google Scholar 

  7. Barron L, Wynn TA. Macrophage activation governs schistosomiasis-induced inflammation and fibrosis. Eur J Immunol. 2011;41:2509–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 2005;5:641–54.

    Article  CAS  PubMed  Google Scholar 

  9. Montoya D, Mehta M, Ferguson BG, Teles RMB, Krutzik SR, Cruz D, et al. Plasticity of antimicrobial and phagocytic programs in human macrophages. Immunology. 2019;156:164–73.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang QZ, Liu YL, Wang YR, Fu LN, Zhang J, Wang XR, et al. Effects of telmisartan on improving leptin resistance and inhibiting hepatic fibrosis in rats with non-alcoholic fatty liver disease. Exp Ther Med. 2017;14:2689–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Imam S, Dar P, Paparodis R, Almotah K, Al-Khudhair A, Hasan SA, et al. Nature of coexisting thyroid autoimmune disease determines success or failure of tumor immunity in thyroid cancer. J Immunother Cancer. 2019;7:3.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Liu RH, Wen Y, Sun HY, Liu CY, Zhang YF, Yang Y, et al. Abdominal paracentesis drainage ameliorates severe acute pancreatitis in rats by regulating the polarization of peritoneal macrophages. World J Gastroenterol. 2018;24:5131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xie L, Yang Y, Meng J, Wen T, Liu J, Xu H. Cationic polysaccharide spermine-pullulan drives tumor associated macrophage towards M1 phenotype to inhibit tumor progression. Int J Biol Macromol. 2019;123:1012–9.

    Article  CAS  PubMed  Google Scholar 

  14. Li J, Xue H, Li T, Chu X, Xin D, Xiong Y, et al. Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE(-/-) mice via miR-let7 mediated infiltration and polarization of M2 macrophage. Biochem Biophys Res Commun. 2019;510:565–72.

    Article  CAS  PubMed  Google Scholar 

  15. Lieber CS, Robins SJ, Li J, DeCarli LM, Mak KM, Fasulo JM, et al. Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon. Gastroenterology. 1994;106:152–9.

    Article  CAS  PubMed  Google Scholar 

  16. Okiyama W, Tanaka N, Nakajima T, Tanaka E, Kiyosawa K, Gonzalez FJ, et al. Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress. J Hepatol. 2009;50:1236–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lieber CS, Leo MA, Aleynik SI, Aleynik MK, DeCarli LM. Polyenylphosphatidylcholine decreases alcohol-induced oxidative stress in the baboon. Alcohol Clin Exp Res. 1997;21:375–9.

    Article  CAS  PubMed  Google Scholar 

  18. Pan W, Hao WT, Xu HW, Qin SP, Li XY, Liu XM, et al. Polyene phosphatidylcholine inhibited the inflammatory response in LPS-stimulated macrophages and ameliorated the adjuvant-induced rat arthritis. Am J Transl Res. 2017;9:4206–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ben-Ami Shor D, Bashi T, Lachnish J, Fridkin M, Bizzaro G, Barshak I, et al. Phosphorylcholine-tuftsin compound prevents development of dextransulfate-sodium-salt induced murine colitis: implications for the treatment of human inflammatory bowel disease. J Autoimmun. 2015;56:111–7.

    Article  CAS  PubMed  Google Scholar 

  20. Zhao H, Dai X, Han X, Liu A, Bao F, Bai R, et al. Borrelia burgdorferi basic membrane protein A initiates proinflammatory chemokine storm in THP 1-derived macrophages via the receptors TLR1 and TLR2. Biomed Pharmacother. 2019;115:108874.

    Article  CAS  PubMed  Google Scholar 

  21. Kumar V. Toll-like receptors in the pathogenesis of neuroinflammation. J Neuroimmunol. 2019;332:16–30.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang J, Diao B, Lin X, Xu J, Tang F. TLR2 and TLR4 mediate an activation of adipose tissue renin-angiotensin system induced by uric acid. Biochimie. 2019;162:125–33.

    Article  CAS  PubMed  Google Scholar 

  23. Jian L, Sun L, Li C, Yu R, Ma Z, Wang X, et al. Interleukin-21 enhances toll-like receptor 2/4-mediated cytokine production via phosphorylation in the STAT3, Akt and p38 MAPK signalling pathways in human monocytic THP-1 cells. Scand J Immunol. 2019;86:e12761.

    Article  CAS  Google Scholar 

  24. Patel CH, Leone RD, Horton MR, Powell JD. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat Rev Drug Discov. 2019;18:669–88.

    Article  CAS  PubMed  Google Scholar 

  25. Koelwyn GJ, Corr EM, Erbay E. Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol. 2018;19:526–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yamada KJ, Kielian T. Biofilm-leukocyte cross-talk: impact on immune polarization and immunometabolism. J Innate Immun. 2019;11(3):280–8.

  27. Shi L, Jiang Q, Bushkin Y, Subbian S, Tyagi S. Biphasic dynamics of macrophage immunometabolism during Mycobacterium tuberculosis infection. mBio. 2019;10(2). https://doi.org/10.1128/mBio.02550-18.

  28. Davis BK. Derivation of macrophages from mouse bone marrow. Methods Mol Biol. 1960;2019:41–55.

    Google Scholar 

  29. Li C, Yang D, Cao X, Wang F, Jiang H, Guo H, et al. LFG-500, a newly synthesized flavonoid, attenuates lipopolysaccharide-induced acute lung injury and inflammation in mice. Biochem Pharmacol. 2016;113:57–69.

    Article  CAS  PubMed  Google Scholar 

  30. Bashi T, Shovman O, Fridkin M, Volkov A, Barshack I, Blank M, et al. Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis. Clin Exp Immunol. 2016;184:19–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.

    Article  CAS  PubMed  Google Scholar 

  32. Moreno-Indias I, Cardona F, Tinahones FJ, Queipo-Ortuno MI. Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front Microbiol. 2014;5:190.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Santiago-Tellez A, Castrillon-Rivera LE, Palma-Ramos A, Bello-Lopez JM, Sainz-Espunes T, Contreras-Paredes A, et al. Keratinocyte infection by Actinomadura madurae triggers an inflammatory response. Trans R Soc Trop Med Hyg. 2019;113:392–8.

    Article  PubMed  CAS  Google Scholar 

  34. Pan W, Xu HW, Hao WT, Sun FF, Qin YF, Hao SS, et al. The excretory-secretory products of Echinococcus granulosus protoscoleces stimulated IL-10 production in B cells via TLR-2 signaling. BMC Immunol. 2018;19:29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Marques CP, Maor Y, de Andrade MS, Rodrigues VP, Benatti BB. Possible evidence of systemic lupus erythematosus and periodontal disease association mediated by toll-like receptors 2 and 4. Clin Exp Immunol. 2016;183:187–92.

    Article  CAS  PubMed  Google Scholar 

  36. Mayhan WG, Arrick DM, Sharpe GM, Sun H. Nitric oxide synthase-dependent responses of the basilar artery during acute infusion of nicotine. Nicotine Tob Res. 2009;11:270–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Higashi Y, Noma K, Yoshizumi M, Kihara Y. Endothelial function and oxidative stress in cardiovascular diseases. Circ J. 2009;73:411–8.

    Article  CAS  PubMed  Google Scholar 

  38. Perveen K, Hanif F, Jawed H, Jamall S, Simjee SU. N-(2-hydroxy phenyl) acetamide: a novel suppressor of toll-like receptors (TLR-2 and TLR-4) in adjuvant-induced arthritic rats. Mol Cell Biochem. 2014;394:67–75.

    Article  CAS  PubMed  Google Scholar 

  39. McGarry T, Biniecka M, Gao W, Cluxton D, Canavan M, Wade S, et al. Resolution of TLR2-induced inflammation through manipulation of metabolic pathways in rheumatoid arthritis. Sci Rep. 2017;7:43165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010;185:605–14.

    Article  CAS  PubMed  Google Scholar 

  41. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Wei X, Song H, Yin L, Rizzo MG, Sidhu R, Covey DF, et al. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature. 2016;539:294–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Namgaladze D, Brune B. Fatty acid oxidation is dispensable for human macrophage IL-4-induced polarization. Biochim Biophys Acta. 1841;2014:1329–35.

    Google Scholar 

  44. Nomura M, Liu J, Rovira II, Gonzalez-Hurtado E, Lee J, Wolfgang MJ, et al. Fatty acid oxidation in macrophage polarization. Nat Immunol. 2016;17:216–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stafstrom CE, Roopra A, Sutula TP. Seizure suppression via glycolysis inhibition with 2-deoxy-D-glucose (2DG). Epilepsia. 2008;49(Suppl 8):97–100.

    Article  PubMed  Google Scholar 

  46. Koenig JB, Cantu D, Low C, Sommer M, Noubary F, Croker D, et al. Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury. JCI Insight. 2019;5. https://doi.org/10.1172/jci.insight.126506.

  47. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.

    Article  CAS  PubMed  Google Scholar 

  48. Towfighi A, Ovbiagele B. Partial peroxisome proliferator-activated receptor agonist angiotensin receptor blockers. Potential multipronged strategy in stroke prevention. Cerebrovasc Dis. 2008;26:106–12.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by grants from the Starting Foundation for Talents of Xuzhou Medical College (No. D2015004), the Jiangsu Planned Projects for Postdoctoral Research Funds (No. 2019 K063), and the Jiangsu Qing Lan Project.

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Author notes

  1. Ting-Ting Feng and Xiao-Ying Yang contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Tongshan Road 209, Xuzhou, 221004, Jiangsu Province, People’s Republic of China

    Ting-Ting Feng, Ye Huang & Qi-Si Lin

  2. Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Tongshan Road 209, Xuzhou, 221004, Jiangsu Province, People’s Republic of China

    Xiao-Ying Yang, Shan-Shan Hao, Fen-Fen Sun & Wei Pan

  3. JOINN Laboratories (Suzhou), Suzhou, 215421, Jiangsu Province, People’s Republic of China

    Wei Pan

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  1. Ting-Ting Feng
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Contributions

Conceived and designed the experiments: WP, TTF, XYY, and QSL. Performed the experiments: TTF and SSH. Analyzed the data: WP, FFT, and YH. Contributed reagents/materials/analysis tools: WP, QSL, and FFS. Wrote the manuscript: WP, FFT, and XYY.

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Correspondence to Qi-Si Lin or Wei Pan.

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Feng, TT., Yang, XY., Hao, SS. et al. TLR-2-mediated metabolic reprogramming participates in polyene phosphatidylcholine-mediated inhibition of M1 macrophage polarization. Immunol Res 68, 28–38 (2020). https://doi.org/10.1007/s12026-020-09125-9

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