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Pyruvate Dehydrogenase Kinase 2 Accelerates Endotoxin Shock by Promoting Mitogen-Activated Protein Kinase Activation

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Abstract

Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.

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AVAILABILITY OF DATA AND MATERIALS

Data that support the results of the present study are available from the corresponding author upon reasonable request.

References

  1. Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G.R. Bernard, J.D. Chiche, C.M. Coopersmith, R.S. Hotchkiss, M.M. Levy, J.C. Marshall, G.S. Martin, S.M. Opal, G.D. Rubenfeld, T. van der Poll, J.L. Vincent, and D.C. Angus. 2016. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315: 801–810. https://doi.org/10.1001/jama.2016.0287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Font, M.D., B. Thyagarajan, and A.K. Khanna. 2020. Sepsis and septic shock - basics of diagnosis, pathophysiology and clinical decision making. Medical Clinics of North America 104: 573–585. https://doi.org/10.1016/j.mcna.2020.02.011.

    Article  PubMed  Google Scholar 

  3. Liu, Z., Y. Fan, Y. Wang, C. Han, Y. Pan, H. Huang, Y. Ye, L. Luo, and Z. Yin. 2008. Dipyrithione inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in macrophages and protects against endotoxic shock in mice. FEBS letters 582: 1643–1650. https://doi.org/10.1016/j.febslet.2008.04.016.

    Article  CAS  PubMed  Google Scholar 

  4. de Padua Lucio K., A.C.S. Rabelo, C.M. Araujo, G.C. Brandao, G.H.B. de Souza, R.G. da Silva, D.M.S. de Souza, A. Talvani, F.S. Bezerra, A.J. Cruz Calsavara, and D.C. Costa. 2018. Anti-inflammatory and antioxidant properties of black mulberry (Morus nigra L.) in a model of LPS-induced sepsis. Oxidative medicine and cellular longevity 2018:5048031. https://doi.org/10.1155/2018/5048031.

  5. Napier, B.A., M. Andres-Terre, L.M. Massis, A.J. Hryckowian, S.K. Higginbottom, K. Cumnock, K.M. Casey, B. Haileselassie, K.A. Lugo, D.S. Schneider, J.L. Sonnenburg, and D.M. Monack. 2019. Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome. Proceedings of the National Academy of Sciences of the United States of America 116: 3688–3694. https://doi.org/10.1073/pnas.1814273116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Delano, M.J., and P.A. Ward. 2016. Sepsis-induced immune dysfunction: Can immune therapies reduce mortality? The Journal of clinical investigation 126: 23–31. https://doi.org/10.1172/JCI82224.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kolaczkowska, E., M. Lelito, E. Kozakiewicz, N. van Rooijen, B. Plytycz, and B. Arnold. 2007. Resident peritoneal leukocytes are important sources of MMP-9 during zymosan peritonitis: Superior contribution of macrophages over mast cells. Immunology letters 113: 99–106. https://doi.org/10.1016/j.imlet.2007.07.017.

    Article  CAS  PubMed  Google Scholar 

  8. Li, X., X. Yao, Y. Zhu, H. Zhang, H. Wang, Q. Ma, F. Yan, Y. Yang, J. Zhang, H. Shi, Z. Ning, J. Dai, Z. Li, C. Li, F. Su, Y. Xue, X. Meng, G. Dong, and H. Xiong. 2019. The caspase inhibitor Z-VAD-FMK alleviates endotoxic shock via inducing macrophages necroptosis and promoting MDSCs-mediated inhibition of macrophages activation. Frontiers in immunology 10: 1824. https://doi.org/10.3389/fimmu.2019.01824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shin, J.S., K.G. Lee, H.H. Lee, H.J. Lee, H.J. An, J.H. Nam, D.S. Jang, and K.T. Lee. 2016. alpha-Solanine Isolated From Solanum Tuberosum L. cv Jayoung Abrogates LPS-induced inflammatory responses via NF-kappaB inactivation in RAW 264.7 macrophages and endotoxin-induced shock model in mice. Journal of cellular biochemistry 117: 2327–2339. https://doi.org/10.1002/jcb.25530.

    Article  CAS  PubMed  Google Scholar 

  10. Medzhitov, R., C.A. Janeway, and Jr. 1997. Innate immunity: The virtues of a nonclonal system of recognition. Cell 91: 295–298. https://doi.org/10.1016/s0092-8674(00)80412-2.

    Article  CAS  PubMed  Google Scholar 

  11. Pearce, E.L., M.C. Poffenberger, C.H. Chang, and R.G. Jones. 2013. Fueling immunity: Insights into metabolism and lymphocyte function. Science 342: 1242454. https://doi.org/10.1126/science.1242454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pearce, E.L., and E.J. Pearce. 2013. Metabolic pathways in immune cell activation and quiescence. Immunity 38: 633–643. https://doi.org/10.1016/j.immuni.2013.04.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McGettrick, A.F., and L.A. O’Neill. 2013. How metabolism generates signals during innate immunity and inflammation. Journal of Biological Chemistry 288: 22893–22898. https://doi.org/10.1074/jbc.R113.486464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roche, T.E., and Y. Hiromasa. 2007. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cellular and Molecular Life Sciences 64: 830–849. https://doi.org/10.1007/s00018-007-6380-z.

    Article  CAS  PubMed  Google Scholar 

  15. Rahman, M.H., A. Bhusal, J.H. Kim, M.K. Jha, G.J. Song, Y. Go, I.S. Jang, I.K. Lee, and K. Suk. 2020. Astrocytic pyruvate dehydrogenase kinase-2 is involved in hypothalamic inflammation in mouse models of diabetes. Nature Communications 11: 5906. https://doi.org/10.1038/s41467-020-19576-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Go, Y., J.Y. Jeong, N.H. Jeoung, J.H. Jeon, B.Y. Park, H.J. Kang, C.M. Ha, Y.K. Choi, S.J. Lee, H.J. Ham, B.G. Kim, K.G. Park, S.Y. Park, C.H. Lee, C.S. Choi, T.S. Park, W.N. Lee, R.A. Harris, and I.K. Lee. 2016. Inhibition of pyruvate dehydrogenase kinase 2 protects against hepatic steatosis through modulation of tricarboxylic acid cycle anaplerosis and ketogenesis. Diabetes 65: 2876–2887. https://doi.org/10.2337/db16-0223.

    Article  CAS  PubMed  Google Scholar 

  17. Sun H., A. Zhu, X. Zhou, F. Wang. 2017. Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel. Oncotarget 8:52642–52650. https://doi.org/10.18632/oncotarget.16991.

  18. He, Z., Z. Li, X. Zhang, K. Yin, W. Wang, Z. Xu, B. Li, L. Zhang, J. Xu, G. Sun, L. Wang, Q. Li, X. Huang, L. Zhang, D. Zhang, H. Xu, and Z. Xu. 2018. MiR-422a regulates cellular metabolism and malignancy by targeting pyruvate dehydrogenase kinase 2 in gastric cancer. Cell Death & Disease 9: 505. https://doi.org/10.1038/s41419-018-0564-3.

    Article  CAS  Google Scholar 

  19. Yagi, Y., M. Kuwahara, J. Suzuki, Y. Imai, and M. Yamashita. 2020. Glycolysis and subsequent mevalonate biosynthesis play an important role in Th2 cell differentiation. Biochemical and Biophysical Research Communications 530: 355–361. https://doi.org/10.1016/j.bbrc.2020.08.009.

    Article  CAS  PubMed  Google Scholar 

  20. Min, B.K., S. Park, H.J. Kang, D.W. Kim, H.J. Ham, C.M. Ha, B.J. Choi, J.Y. Lee, C.J. Oh, E.K. Yoo, H.E. Kim, B.G. Kim, J.H. Jeon, D.Y. Hyeon, D. Hwang, Y.H. Kim, C.H. Lee, T. Lee, J.W. Kim, Y.K. Choi, K.G. Park, A. Chawla, J. Lee, R.A. Harris, and I.K. Lee. 2019. Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype. Frontiers in immunology 10: 944. https://doi.org/10.3389/fimmu.2019.00944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Na, Y.R., D. Jung, J. Song, J.W. Park, J.J. Hong, and S.H. Seok. 2020. Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages. Journal of Molecular Cell Biology 12: 543–555. https://doi.org/10.1093/jmcb/mjz113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meyers, A.K., Z. Wang, W. Han, Q. Zhao, M. Zabalawi, J. Liu, R.K. Manne, H.K. Lin, C.M. Furdui, J.W. Locasale, and C.M. McCall. 2021. Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.

  23. Tripathi, S., D. Bruch, and D.S. Kittur. 2008. Ginger extract inhibits LPS induced macrophage activation and function. BMC Complementary and Alternative Medicine 8: 1. https://doi.org/10.1186/1472-6882-8-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Morrell, J.A., J. Orme, R.J. Butlin, T.E. Roche, R.M. Mayers, and E. Kilgour. 2003. AZD7545 is a selective inhibitor of pyruvate dehydrogenase kinase 2. Biochemical Society transactions 31: 1168–1170. https://doi.org/10.1042/bst0311168.

    Article  CAS  PubMed  Google Scholar 

  25. Mayers, R.M., R.J. Butlin, E. Kilgour, B. Leighton, D. Martin, J. Myatt, J.P. Orme, and B.R. Holloway. 2003. AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats. Biochemical Society transactions 31: 1165–1167. https://doi.org/10.1042/bst0311165.

    Article  CAS  PubMed  Google Scholar 

  26. Cesi, G., G. Walbrecq, A. Zimmer, S. Kreis, and C. Haan. 2017. ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells. Molecular cancer 16: 102. https://doi.org/10.1186/s12943-017-0667-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van der Poll, T., F.L. van de Veerdonk, B.P. Scicluna, and M.G. Netea. 2017. The immunopathology of sepsis and potential therapeutic targets. Nature Reviews Immunology 17: 407–420. https://doi.org/10.1038/nri.2017.36.

    Article  CAS  PubMed  Google Scholar 

  28. Prescott, H.C., and D.C. Angus. 2018. Enhancing recovery from sepsis: A review. JAMA 319: 62–75. https://doi.org/10.1001/jama.2017.17687.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kaukonen, K.M., M. Bailey, S. Suzuki, D. Pilcher, and R. Bellomo. 2014. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311: 1308–1316. https://doi.org/10.1001/jama.2014.2637.

    Article  CAS  PubMed  Google Scholar 

  30. Rezinciuc, S., L. Bezavada, A. Bahadoran, S. Duan, R. Wang, D. Lopez-Ferrer, D. Finkelstein, M.A. McGargill, D.R. Green, L. Pasa-Tolic, and H.S. Smallwood. 2020. Dynamic metabolic reprogramming in dendritic cells: An early response to influenza infection that is essential for effector function. PLoS Pathogens 16: e1008957. https://doi.org/10.1371/journal.ppat.1008957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Soto-Heredero, G., Gomez de Las, M.M. Heras, E. Gabande-Rodriguez, J. Oller, and M. Mittelbrunn. 2020. Glycolysis - a key player in the inflammatory response. The FEBS journal 287: 3350–3369. https://doi.org/10.1111/febs.15327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bajotto, G., T. Murakami, M. Nagasaki, B. Qin, Y. Matsuo, K. Maeda, M. Ohashi, Y. Oshida, Y. Sato, and Y. Shimomura. 2006. Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: Induction by elevated levels of free fatty acids. Metabolism 55: 317–323. https://doi.org/10.1016/j.metabol.2005.09.014.

    Article  CAS  PubMed  Google Scholar 

  33. Arora, H., S.M. Wilcox, L.A. Johnson, L. Munro, B.A. Eyford, C.G. Pfeifer, I. Welch, and W.A. Jefferies. 2019. The ATP-binding cassette gene ABCF1 functions as an E2 ubiquitin-conjugating enzyme controlling macrophage polarization to dampen lethal septic shock. Immunity 50 (418–431): e416. https://doi.org/10.1016/j.immuni.2019.01.014.

    Article  CAS  Google Scholar 

  34. Fan, M., X. Li, X. Gao, L. Dong, G. Xin, L. Chen, J. Qiu, and Y. Xu. 2019. LPS Induces preeclampsia-like phenotype in rats and HTR8/SVneo cells dysfunction through TLR4/p38 MAPK pathway. Frontiers in Physiology 10: 1030. https://doi.org/10.3389/fphys.2019.01030.

    Article  PubMed  PubMed Central  Google Scholar 

  35. de Oliveira, R.G., Castilho G. R. de Campos, A.L. da Cunha, F. Miyajima, and Martins D. T. de Oliveira. 2017. Dilodendron bipinnatum Radlk. inhibits pro-inflammatory mediators through the induction of MKP-1 and the down-regulation of MAPKp38/JNK/NF-kappaB pathways and COX-2 in LPS-activated RAW 264.7 cells. Journal of Ethnopharmacology 202: 127–137. https://doi.org/10.1016/j.jep.2017.02.026.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGEMENTS

We thank the laboratory students at Jining Medical University (Lina Jing, Dalei Cheng, Hongyan Cheng, and Chenyu Li) for their helpful contribution under the guidance of Huabao Xiong. We also thank Editage (www.editage.com) for English language editing.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81874169); the Shandong Provincial Natural Science Foundation, China (No. ZR2020MH163 and ZR2020KH033); the Project of the Medical and Health Technology Development Program in Shandong Province, China (No. 2019WS356); the Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation in Jining Medical University (No. JYHL2021MS06); and the NSFC Cultivation Project of Jining Medical University, China (No. JYP2019KJ23).

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  1. Chunxia Li and Jun Dai equally contributed to this work.

Authors and Affiliations

  1. Institute of Immunology and Molecular Medicine, Basic Medical School, Jining Medical University, Jining, 272067, Shandong, China

    Chunxia Li, Jun Dai, Guanjun Dong, Xin Zhang, Junfeng Zhang, Fenglian Yan, Hui Zhang, Changying Wang, Mingsheng Zhao, Zhaochen Ning, Qun Ma, Hui Shi, Zhihua Li & Huabao Xiong

  2. Department of Pediatric Dentistry, Jining Stomatological Hospital, Jining, 272067, Shandong, China

    Chuanbin Liu

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Contributions

Huabao Xiong, Chunxia Li, Jun Dai, and Guanjun Dong contributed to study concept and design. Huabao Xiong directed the study, contributed to data interpretation, and drafted and critically revised the manuscript. Huabao Xiong, Chunxia Li, Jun Dai, and Junfeng Zhang obtained funding. Chunxia Li, Chuanbin Liu, Xin Zhang, and Junfeng Zhang performed all experiments in vitro and carried out primary analyses. All other experiments and mouse manipulation were performed by Chunxia Li, Zhaochen Ning, Qun Ma, and Zhihua Li. Fenglian Yan and Hui Zhang carried out histopathological interpretation. Changying Wang and Mingsheng Zhao carried out FACS-adjusted and compositional analysis. Chunxia Li, Chuanbin Liu, Guanjun Dong, and Hui Shi contributed to manuscript preparation and data analyses. Jun Dai and Chunxia Li contributed equally to this work. All authors read and approved the final manuscript.

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Correspondence to Huabao Xiong.

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Li, C., Dai, J., Liu, C. et al. Pyruvate Dehydrogenase Kinase 2 Accelerates Endotoxin Shock by Promoting Mitogen-Activated Protein Kinase Activation. Inflammation 46, 418–431 (2023). https://doi.org/10.1007/s10753-022-01744-8

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