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Inhibition of γδ T Cells Alleviates Blood–Brain Barrier in Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

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Abstract

Ischemia/reperfusion (I/R) injury is the leading cause of death following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). γδT cells are suggested to aggravate blood–brain barrier (BBB) injury in various pathological processes. We herein investigate the effects of γδT cells inhibitor (UC7-13D5) against I/R injury post-CA/CPR. C57BL/6 mice were subjected to CA through injection of KCL (70 μL of 0.5 mol/L) and cessation of mechanical ventilation followed by CPR. Flow cytometry was performed to measure the proportion of CD3-positive cells after intraperitoneal injection of 200 μg UC7-13D5 at 6 h, 24 h, and 48 h post-resuscitation into mice. Neurological scores and modified neurological severity scores were assessed to examine neurological functions. Brain edema was estimated via brain water content measurements. Immunohistochemistry of caspase-3 and immunofluorescence staining of claudin-1, ZO-1 and CD31 were performed to detect neuronal apoptosis, BBB integrity and angiogenesis. Microvascular morphology in the cortical area was assessed via H&E staining. Oxidative stress was determined by measuring malondialdehyde, myeloperoxidase, xanthine oxidase, superoxide dismutase, and glutathione peroxidase activities. Western blotting was performed to measure the protein levels of Nuclear factor-E2-related factor 2 (Nrf2) and Heme oxygenase-1 (HO-1). UC7-13D5 effectively depleted γδT cells. Inhibition of γδT cells improved neurological deficits and reduced brain edema post-CA/CPR. γδT cells depletion attenuated neuronal apoptosis, BBB disruption and oxidative stress and promoted angiogenesis following CA/CPR. Inhibition of γδT cells facilitated the activation of the Nrf2/HO-1 pathway in CA/CPR-induced mice. Inhibition of γδT cells alleviates neurological deficits and cerebral edema in mice with CA/CPR by inhibiting neuronal apoptosis, BBB disruption and oxidative stress, and promoting angiogenesis via activation of the Nrf2/HO-1 pathway.

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Data Availability

Data supporting this research article are available from the corresponding author or first author on reasonable request.

References

  1. Field, J. M., Hazinski, M. F., Sayre, M. R., Chameides, L., Schexnayder, S. M., Hemphill, R., Samson, R. A., Kattwinkel, J., Berg, R. A., Bhanji, F., & Cave, D. M. (2010). Part 1: Executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 122(18 Suppl 3), S640–S656.

    PubMed  Google Scholar 

  2. Xu, F., Zhang, Y., & Chen, Y. (2017). Cardiopulmonary resuscitation training in China: Current situation and future development. JAMA Cardiology., 2(5), 469–470.

    Article  PubMed  Google Scholar 

  3. Andersen, L. W., Holmberg, M. J., Berg, K. M., Donnino, M. W., & Granfeldt, A. (2019). In-hospital cardiac arrest: A review. JAMA, 321(12), 1200–1210.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wallmuller, C., Meron, G., Kurkciyan, I., Schober, A., Stratil, P., & Sterz, F. (2012). Causes of in-hospital cardiac arrest and influence on outcome. Resuscitation, 83(10), 1206–1211.

    Article  PubMed  Google Scholar 

  5. Legriel, S., Bougouin, W., Chocron, R., Beganton, F., Lamhaut, L., Aissaoui, N., Deye, N., Jost, D., Mekontso-Dessap, A., Vieillard-Baron, A., & Marijon, E. (2018). Early in-hospital management of cardiac arrest from neurological cause: Diagnostic pitfalls and treatment issues. Resuscitation, 132, 147–155.

    Article  PubMed  Google Scholar 

  6. Hasselqvist-Ax, I., Riva, G., Herlitz, J., Rosenqvist, M., Hollenberg, J., Nordberg, P., Ringh, M., Jonsson, M., Axelsson, C., Lindqvist, J., & Karlsson, T. (2015). Early cardiopulmonary resuscitation in out-of-hospital cardiac arrest. The New England Journal of Medicine, 372(24), 2307–2315.

    Article  CAS  PubMed  Google Scholar 

  7. Bircher, N. G., Chan, P. S., & Xu, Y. (2019). Delays in cardiopulmonary resuscitation, defibrillation, and epinephrine administration all decrease survival in in-hospital cardiac arrest. Anesthesiology, 130(3), 414–422.

    Article  CAS  PubMed  Google Scholar 

  8. Andresen, M., Gazmuri, J. T., Marín, A., Regueira, T., & Rovegno, M. (2015). Therapeutic hypothermia for acute brain injuries. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 23, 42.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Thom, T., Haase, N., Rosamond, W., Howard, V. J., Rumsfeld, J., Manolio, T., Zheng, Z. J., Flegal, K., O’Donnell, C., & Kittner, S. (2006). Heart disease and stroke statistics–2006 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 113(6), e85-151.

    PubMed  Google Scholar 

  10. Liang, L., Shao, W., Shu, T., Zhang, Y., Xu, S., Guo, L., Zhou, Y., Huang, H., & Sun, P. (2019). Xuezhikang improves the outcomes of cardiopulmonary resuscitation in rats by suppressing the inflammation response through TLR4/NF-κB pathway. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 114, 108817.

    Article  Google Scholar 

  11. Metter, R. B., Rittenberger, J. C., Guyette, F. X., & Callaway, C. W. (2011). Association between a quantitative CT scan measure of brain edema and outcome after cardiac arrest. Resuscitation, 82(9), 1180–1185.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hayman, E. G., Patel, A. P., Kimberly, W. T., Sheth, K. N., & Simard, J. M. (2018). Cerebral Edema after cardiopulmonary resuscitation: A therapeutic target following cardiac arrest? Neurocritical Care, 28(3), 276–287.

    Article  CAS  PubMed  Google Scholar 

  13. Sharma, H. S., Miclescu, A., & Wiklund, L. (2011). Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: A light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. Journal of Neural Transmission (Vienna, Austria: 1996), 118(1), 87–114.

    Article  PubMed  Google Scholar 

  14. Abdullahi, W., Tripathi, D., & Ronaldson, P. T. (2018). Blood-brain barrier dysfunction in ischemic stroke: Targeting tight junctions and transporters for vascular protection. American Journal of Physiology Cell Physiology., 315(3), C343–C356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. De Rosa, S. C., Andrus, J. P., Perfetto, S. P., Mantovani, J. J., Herzenberg, L. A., Herzenberg, L. A., & Roederer, M. (2004). Ontogeny of gamma delta T cells in humans. Journal of Immunology (Baltimore, Md: 1950), 172(3), 1637–1645.

    Article  PubMed  Google Scholar 

  16. Born, W. K., Yin, Z., Hahn, Y. S., Sun, D., & O’Brien, R. L. (2010). Analysis of gamma delta T cell functions in the mouse. Journal of Immunology (Baltimore, Md: 1950), 184(8), 4055–4061.

    Article  CAS  PubMed  Google Scholar 

  17. Fichtner, A. S., Ravens, S., & Prinz, I. (2020). Human γδ TCR repertoires in health and disease. Cells, 9(4), 800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Born, W. K., Kemal Aydintug, M., & O’Brien, R. L. (2013). Diversity of γδ T-cell antigens. Cellular & Molecular Immunology, 10(1), 13–20.

    Article  CAS  Google Scholar 

  19. Castro, C. D., Boughter, C. T., Broughton, A. E., Ramesh, A., & Adams, E. J. (2020). Diversity in recognition and function of human γδ T cells. Immunological Reviews, 298(1), 134–152.

    Article  CAS  PubMed  Google Scholar 

  20. Brandes, M., Willimann, K., & Moser, B. (2005). Professional antigen-presentation function by human gammadelta T Cells. Science (New York, NY), 309(5732), 264–268.

    Article  CAS  Google Scholar 

  21. Vantourout, P., & Hayday, A. (2013). Six-of-the-best: Unique contributions of γδ T cells to immunology. Nature Reviews Immunology, 13(2), 88–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dong, X., Zhang, X., Li, C., Chen, J., Xia, S., Bao, X., Ge, J., Cao, X., & Xu, Y. (2022). γδ T cells aggravate blood-brain-barrier injury via IL-17A in experimental ischemic stroke. Neuroscience Letters, 776, 136563.

    Article  CAS  PubMed  Google Scholar 

  23. McCandless, E. E., Budde, M., Lees, J. R., Dorsey, D., Lyng, E., & Klein, R. S. (2009). IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. Journal of Immunology (Baltimore, Md: 1950), 183(1), 613–620.

    Article  CAS  PubMed  Google Scholar 

  24. Brigas, H. C., Ribeiro, M., Coelho, J. E., Gomes, R., Gomez-Murcia, V., Carvalho, K., Faivre, E., Costa-Pereira, S., Darrigues, J., de Almeida, A. A., & Buée, L. (2021). IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Reports, 36(9), 109574.

    Article  CAS  PubMed  Google Scholar 

  25. Ishigami, M., Nishimura, H., Yoshioka, K., Kakumu, S., & Yoshikai, Y. (1999). The role of intrahepatic gammadelta-T cells for liver injury induced by Salmonella infection in mouse. Microbiology and Immunology, 43(5), 461–469.

    Article  CAS  PubMed  Google Scholar 

  26. Hou, Y., Wang, Y., He, Q., Li, L., Xie, H., Zhao, Y., & Zhao, J. (2018). Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury. Behavioural Brain Research, 336, 32–39.

    Article  CAS  PubMed  Google Scholar 

  27. Kobayashi, Y., Kawai, K., Ito, K., Honda, H., Sobue, G., & Yoshikai, Y. (1997). Aggravation of murine experimental allergic encephalomyelitis by administration of T-cell receptor gammadelta-specific antibody. Journal of Neuroimmunology, 73(1–2), 169–174.

    Article  CAS  PubMed  Google Scholar 

  28. Gao, C. J., Li, J. P., Wang, W., Lü, B. C., Niu, L., Zhu, C., Wei, Y. Y., Zhang, T., Wu, S. X., Chai, W., & Li, Y. Q. (2010). Effects of intracerebroventricular application of the delta opioid receptor agonist [D-Ala2, D-Leu5] enkephalin on neurological recovery following asphyxial cardiac arrest in rats. Neuroscience, 168(2), 531–542.

    Article  CAS  PubMed  Google Scholar 

  29. Deng, H., Tang, Z., Tuo, P., Wu, R., Jia, S., Zhao, X., Huang, D., Gao, Y., & Lan, Z. (2022). Shenfu injection protects brain injury in rats with cardiac arrest through Nogo/NgR pathway. Analytical Cellular Pathology (Amsterdam), 2022, 4588999.

    PubMed  Google Scholar 

  30. Blanco, Y. C., Farias, A. S., Goelnitz, U., Lopes, S. C., Arrais-Silva, W. W., Carvalho, B. O., Amino, R., Wunderlich, G., Santos, L. M., Giorgio, S., & Costa, F. T. (2008). Hyperbaric oxygen prevents early death caused by experimental cerebral malaria. PLoS ONE, 3(9), e3126.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hammerich, L., Bangen, J. M., Govaere, O., Zimmermann, H. W., Gassler, N., Huss, S., Liedtke, C., Prinz, I., Lira, S. A., Luedde, T., & Roskams, T. (2014). Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology (Baltimore, MD), 59(2), 630–642.

    Article  CAS  PubMed  Google Scholar 

  32. Hatakeyama, M., Ninomiya, I., & Kanazawa, M. (2020). Angiogenesis and neuronal remodeling after ischemic stroke. Neural Regeneration Research, 15(1), 16–19.

    Article  PubMed  Google Scholar 

  33. Granger, D. N., & Kvietys, P. R. (2015). Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox biology, 6, 524–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Abdel-Magied, N., Shedid, S. M., & Ahmed, A. G. (2019). Mitigating effect of biotin against irradiation-induced cerebral cortical and hippocampal damage in the rat brain tissue. Environmental Science and Pollution Research International, 26(13), 13441–13452.

    Article  CAS  PubMed  Google Scholar 

  35. Lorente, L., Martin, M. M., Abreu-Gonzalez, P., Ramos, L., Argueso, M., Caceres, J. J., Solé-Violán, J., Lorenzo, J. M., Molina, I., & Jiménez, A. (2015). Association between serum malondialdehyde levels and mortality in patients with severe brain trauma injury. Journal of Neurotrauma, 32(1), 1–6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yu, G., Liang, Y., Huang, Z., Jones, D. W., Pritchard, K. A., Jr., & Zhang, H. (2016). Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke. Journal of Neuroinflammation., 13(1), 119.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chen, L., Ma, S., Shi, M., Wang, Q., & Miao, Y. (2022). A new nitronyl nitroxide radical with salicylic acid framework attenuates blood-brain barrier disruption and oxidative stress in a rat model of middle cerebral artery occlusion. NeuroReport, 33(3), 129–136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018). The KEAP1-NRF2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiological Reviews, 98(3), 1169–1203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Not applicable.

Funding

The work was supported by Health Commission of Hubei Province Scientific Research Project (No. WJ2021F114), Health Commission of Hubei Province Scientific Research Project (No. WJ2019F165), and Internal Medicine Research Project of Hubei Hospital of Traditional Chinese Medicine (No. 2021YJKT-27).

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Authors and Affiliations

  1. Department of Anesthesiology, Huazhong University of Science and Technology Union Dongxihu Hospital, People’s Hospital of Wuhan Dongxihu District, Wuhan, 430040, Hubei, China

    Yeqiu Li

  2. Department of Anesthesiology, Hubei Hospital of Traditional Chinese Medicine, No. 4, Garden Hill, Yanzhi Road, Wuchang District, Wuhan, 430061, Hubei, China

    Ting Wu & Cheng Guo

  3. Department of Anesthesiology, The Affiliated Hospital of Hubei Traditional Chinese Medicine University, Wuhan, 430061, China

    Ting Wu & Cheng Guo

  4. Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430061, China

    Ting Wu & Cheng Guo

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  1. Yeqiu Li
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Correspondence to Ting Wu or Cheng Guo.

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Li, Y., Wu, T. & Guo, C. Inhibition of γδ T Cells Alleviates Blood–Brain Barrier in Cardiac Arrest and Cardiopulmonary Resuscitation in Mice. Mol Biotechnol 65, 2061–2070 (2023). https://doi.org/10.1007/s12033-023-00705-2

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