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PD-L1 Regulates Inflammation in LPS-Induced Lung Epithelial Cells and Vascular Endothelial Cells by Interacting with the HIF-1α Signaling Pathway

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A Correction to this article was published on 28 January 2022

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Abstract

Sepsis-induced lung injury was the most common cause of death in patients. This study aimed to investigate whether PD-L1 regulates the inflammation in LPS-induced lung epithelial cells and vascular endothelial cells by interacting with the HIF-1α signaling pathway. Sepsis-induced lung injury mice were constructed by cecal ligation and puncture (CLP) procedure, and lipopolysaccharide (LPS)-induced lung epithelial cells and vascular endothelial cells simulate the sepsis-induced lung injury model in vitro. Hematoxylin-eosin (HE) staining detected the morphological changes of the lung tissues, and immunohistochemistry (IHC) detected the PD-L1 expression in lung tissues. Bicinchoninic acid (BCA) assay determined the protein concentration in bronchial alveolar lavage fluid (BALF). The number of PD-1 (+) cells in blood was detected by flow cytometry. The apoptosis in lung tissues and LPS-induced cells was analyzed by TUNEL assay. The inflammatory factor levels and HIF-1α in lung tissues and LPS-induced cells were analyzed by ELISA. The transfection effects of KD-PDL1 or KD-HIF1A in lung epithelial cells and vascular endothelial cells were confirmed by qRT-PCR analysis. The protein expression related to the PD-L1- and HIF-1α-related pathway was determined by Western blot analysis. As a result, LMT-28, as an IL-6 inhibitor, alleviated lung injury and suppressed the apoptosis and inflammation in lung tissues in BALF and the number of PD-1 (+) cells in blood. Sepsis-induced lung injury activated the PD-L1- and HIF-1α-related pathway, while LMT-28 could not completely inhibit the pathway. In addition, downregulation of PD-L1 or downregulation of HIF-1α suppressed the apoptosis and alleviated the inflammation in LPS-induced lung epithelial cells and vascular endothelial cells. Downregulation of PD-L1 had significant effects on lung epithelial cells but had greater effects on vascular endothelial cells. Downregulation of HIF-1α could decrease PD-L1 expression, and downregulation of PD-L1 could also suppress the protein expression of HIF-1α and related pathways. In conclusion, downregulation of PD-L1 alleviated the inflammation in LPS-induced lung epithelial cells and vascular endothelial cells by suppressing the HIF-1α signaling pathway.

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References

  1. Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, et al. 2016. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315: 801–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bellani, G., J.G. Laffey, T. Pham, E. Fan, L. Brochard, A. Esteban, et al. 2016. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315: 788–800.

    Article  CAS  PubMed  Google Scholar 

  3. Fragoso, I.T., E.L. Ribeiro, F.O. Gomes, M.A. Donato, A.K. Silva, A.C. Oliveira, et al. 2017. Diethylcarbamazine attenuates LPS-induced acute lung injury in mice by apoptosis of inflammatory cells. Pharmacological Reports 69: 81–89.

    Article  CAS  PubMed  Google Scholar 

  4. Hu, X., S. Liu, J. Zhu, and H. Ni. 2019. Dachengqi decoction alleviates acute lung injury and inhibits inflammatory cytokines production through TLR4/NF-κB signaling pathway in vivo and in vitro. Journal of Cellular Biochemistry 120: 8956–8964.

    Article  CAS  PubMed  Google Scholar 

  5. Lei, J., Y. Wei, P. Song, Y. Li, T. Zhang, Q. Feng, et al. 2018. Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress. European Journal of Pharmacology 818: 110–114.

    Article  CAS  PubMed  Google Scholar 

  6. Keir, M.E., M.J. Butte, G.J. Freeman, and A.H. Sharpe. 2008. PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology 26: 677–704.

    Article  CAS  PubMed  Google Scholar 

  7. Lomas-Neira, J., S.F. Monaghan, X. Huang, E.A. Fallon, C.S. Chung, and A. Ayala. 2018. Novel role for PD-1:PD-L1 as mediator of pulmonary vascular endothelial cell functions in pathogenesis of indirect ARDS in mice. Frontiers in Immunology 9: 3030.

    Article  CAS  PubMed  Google Scholar 

  8. Sun, B., X. Li, G. Zheng, T. Dong, Y. Li, H. Li, et al. 2019. Blockade of programmed death-ligand 1 attenuates indirect acute lung injury in mice through targeting endothelial cells but not epithelial cells. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 31: 37–43.

    PubMed  Google Scholar 

  9. Taylor, C.T., and J.C. McElwain. 2010. Ancient atmospheres and the evolution of oxygen sensing via the hypoxia-inducible factor in metazoans. Physiology (Bethesda, Md.) 25: 272–279.

    CAS  Google Scholar 

  10. Eltzschig, H.K., D.L. Bratton, and S.P. Colgan. 2014. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nature Reviews Drug Discovery 13: 852–869.

    Article  CAS  PubMed  Google Scholar 

  11. Semenza, G.L. 2009. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda, Md.) 24: 97–106.

    CAS  Google Scholar 

  12. Eltzschig, H.K., and P. Carmeliet. 2011. Hypoxia and inflammation. The New England Journal of Medicine 364: 656–665.

    Article  CAS  PubMed  Google Scholar 

  13. Ouyang, H., Y. Tan, Q. Li, F. Xia, X. Xiao, S. Zheng, et al. 2020. MicroRNA-208-5p regulates myocardial injury of sepsis mice via targeting SOCS2-mediated NF-κB/HIF-1α pathway. International Immunopharmacology 81: 106204.

    Article  CAS  PubMed  Google Scholar 

  14. Chang, Y.L., C.Y. Yang, M.W. Lin, C.T. Wu, and P.C. Yang. 2016. High co-expression of PD-L1 and HIF-1α correlates with tumour necrosis in pulmonary pleomorphic carcinoma. European Journal of Cancer (Oxford, England : 1990) 60: 125–135.

    Article  CAS  Google Scholar 

  15. Chen, T.C., C.T. Wu, C.P. Wang, W.L. Hsu, T.L. Yang, P.J. Lou, et al. 2015. Associations among pretreatment tumor necrosis and the expression of HIF-1α and PD-L1 in advanced oral squamous cell carcinoma and the prognostic impact thereof. Oral Oncology 51: 1004–1010.

    Article  CAS  PubMed  Google Scholar 

  16. Barsoum, I.B., C.A. Smallwood, D.R. Siemens, and C.H. Graham. 2014. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Research 74: 665–674.

    Article  CAS  PubMed  Google Scholar 

  17. Xu, L., X. Chen, M. Shen, D.R. Yang, L. Fang, G. Weng, et al. 2018. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Molecular Oncology 12: 269–286.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang, N., Y. Zeng, W. Du, J. Zhu, D. Shen, Z. Liu, et al. 2016. The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. International Journal of Oncology 49: 1360–1368.

    Article  CAS  PubMed  Google Scholar 

  19. Gao, X., Y. Li, H. Wang, C. Li, and J. Ding. 2017. Inhibition of HIF-1α decreases expression of pro-inflammatory IL-6 and TNF-α in diabetic retinopathy. Acta Ophthalmologica 95: e746–e750.

    Article  CAS  PubMed  Google Scholar 

  20. Selvendiran, K., A. Bratasz, M.L. Kuppusamy, M.F. Tazi, B.K. Rivera, and P. Kuppusamy. 2009. Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3. International Journal of Cancer 125: 2198–2204.

    Article  CAS  PubMed  Google Scholar 

  21. Jung, J.E., H.G. Lee, I.H. Cho, D.H. Chung, S.H. Yoon, Y.M. Yang, et al. 2005. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. The FASEB Journal 19: 1296–1298.

    Article  CAS  PubMed  Google Scholar 

  22. Jiang, Q., Z. Chen, and H. Jiang. 2020. Flufenamic acid alleviates sepsis-induced lung injury by up-regulating CBR1. Drug Development Research 81: 885–892.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, Y., J. Li, J. Lou, Y. Zhou, L. Bo, J. Zhu, et al. 2011. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Critical Care (London, England) 15: R70.

    Article  Google Scholar 

  24. Hotchkiss, R., G. Monneret, and D. Payen. 2013. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews Immunology 13: 862–874.

    Article  CAS  PubMed  Google Scholar 

  25. Huang, X., F. Venet, Y.L. Wang, A. Lepape, Z. Yuan, Y. Chen, et al. 2009. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proceedings of the National Academy of Sciences of the United States of America 106: 6303–6308.

    Article  CAS  PubMed  Google Scholar 

  26. Huang, X., Y. Chen, C.S. Chung, Z. Yuan, S.F. Monaghan, F. Wang, et al. 2014. Identification of B7-H1 as a novel mediator of the innate immune/proinflammatory response as well as a possible myeloid cell prognostic biomarker in sepsis. Journal of Immunology 192: 1091–1099.

    Article  CAS  Google Scholar 

  27. Brahmer, J.R., S.S. Tykodi, L.Q. Chow, W.J. Hwu, S.L. Topalian, P. Hwu, et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The New England Journal of Medicine 366: 2455–2465.

    Article  CAS  PubMed  Google Scholar 

  28. Hotchkiss, R.S., and L.L. Moldawer. 2014. Parallels between cancer and infectious disease. The New England Journal of Medicine 371: 380–383.

    Article  PubMed  Google Scholar 

  29. Li, X.H., X. Gong, L. Zhang, R. Jiang, H.Z. Li, M.J. Wu, et al. 2013. Protective effects of polydatin on septic lung injury in mice via upregulation of HO-1. Mediators of Inflammation 2013: 354087.

    Article  PubMed  Google Scholar 

  30. Zhu, J., J. Wang, Y. Sheng, Y. Zou, L. Bo, F. Wang, et al. 2012. Baicalin improves survival in a murine model of polymicrobial sepsis via suppressing inflammatory response and lymphocyte apoptosis. PLoS One 7: e35523.

    Article  CAS  PubMed  Google Scholar 

  31. Zhu, W., R. Bao, X. Fan, T. Tao, J. Zhu, J. Wang, et al. 2013. PD-L1 blockade attenuated sepsis-induced liver injury in a mouse cecal ligation and puncture model. Mediators of Inflammation 2013: 361501.

    Article  PubMed  Google Scholar 

  32. Kumari, N., B.S. Dwarakanath, A. Das, and A.N. Bhatt. 2016. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biology 37: 11553–11572.

    Article  CAS  PubMed  Google Scholar 

  33. Zerdes, I., A. Matikas, J. Bergh, G. Rassidakis, and T. Foukakis. 2018. Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene 37: 4639–4661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miao, D., C.A. Margolis, W. Gao, M.H. Voss, W. Li, D.J. Martini, et al. 2018. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359: 801–806.

    Article  CAS  PubMed  Google Scholar 

  35. Wölfle, S., J. Strebovsky, H. Bartz, A. Sähr, C. Arnold, C. Kaiser, et al. 2011. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. European Journal of Immunology 41: 413–424.

    Article  PubMed  Google Scholar 

  36. Zhang, W., Y. Liu, Z. Yan, H. Yang, W. Sun, Y. Yao, et al. 2020. IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma. Journal for Immunotherapy of Cancer 8: e000285.

    Article  PubMed  Google Scholar 

  37. Liu, Z., R. Xi, Z. Zhang, W. Li, Y. Liu, F. Jin, et al. 2014. 4-Hydroxyphenylacetic acid attenuated inflammation and edema via suppressing HIF-1α in seawater aspiration-induced lung injury in rats. International Journal of Molecular Sciences 15: 12861–12884.

    Article  CAS  PubMed  Google Scholar 

  38. Huang, J.J., J. Xia, L.L. Huang, and Y.C. Li. 2019. HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. Molecular Medicine Reports 20: 3424–3432.

    CAS  PubMed  Google Scholar 

  39. Noman, M.Z., G. Desantis, B. Janji, M. Hasmim, S. Karray, P. Dessen, et al. 2014. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. The Journal of Experimental Medicine 211: 781–790.

    Article  CAS  PubMed  Google Scholar 

  40. Mittendorf, E.A., A.V. Philips, F. Meric-Bernstam, N. Qiao, Y. Wu, S. Harrington, et al. 2014. PD-L1 expression in triple-negative breast cancer. Cancer Immunology Research 2: 361–370.

    Article  CAS  PubMed  Google Scholar 

  41. Soliman, H., F. Khalil, and S. Antonia. 2014. PD-L1 expression is increased in a subset of basal type breast cancer cells. PLoS One 9: e88557.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Respiratory Intensive Care Unit (ICU), The First Affiliated Hospital of Zhengzhou University, No. 1 JianShe East Road, Zhengzhou, 450000, Henan Province, China

    Shilong Zhao, Jing Gao, Jing Li, Shilei Wang, Congcong Yuan & Qiuhong Liu

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  1. Shilong Zhao
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  2. Jing Gao
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  6. Qiuhong Liu
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Contributions

QL and SZ conceived and designed the experiments, and SZ conducted the whole experiment in this study with the help of JG and JL. SW and CY participated in data arrangement. SZ wrote the paper, and QL corrected the error in the manuscript.

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Correspondence to Qiuhong Liu.

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Zhao, S., Gao, J., Li, J. et al. PD-L1 Regulates Inflammation in LPS-Induced Lung Epithelial Cells and Vascular Endothelial Cells by Interacting with the HIF-1α Signaling Pathway. Inflammation 44, 1969–1981 (2021). https://doi.org/10.1007/s10753-021-01474-3

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  • DOI: https://doi.org/10.1007/s10753-021-01474-3

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