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Dexamethasone, but Not Vitamin D or A, Dampens the Inflammatory Neutrophil Response to Protect At-risk COVID-19 Patients

  • Florianne M.J. Hafkamp (Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection & Immunity, University of Amsterdam) ;
  • Sanne Mol (Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection & Immunity, University of Amsterdam) ;
  • Iris Waque (Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection & Immunity, University of Amsterdam) ;
  • Esther C. De Jong (Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection & Immunity, University of Amsterdam)
  • Received : 2022.01.26
  • Accepted : 2022.04.10
  • Published : 2022.08.31
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Abstract

Dexamethasone (DEX) was the first drug shown to save lives of critically ill coronavirus disease 2019 (COVID-19) patients suffering from respiratory distress. A hyperactivated state of neutrophils was found in COVID-19 patients compared to non-COVID pneumonia cases. Given the beneficial effects of DEX in COVID-19 patients, we investigated the effects of DEX and of other immunomodulatory drugs vitamin D3 (VD3) and retinoic acid (RA) on neutrophil function. DEX, but not VD3 or RA, significantly inhibited all tested aspects of neutrophil function, e.g., degranulation, intracellular ROS production, CXCL8 release and NETosis. Interestingly, RA displayed the opposite effect by significantly increasing both CXCL8 and NET release by neutrophils. Taken together, these data suggest that the lower COVID-19 mortality in DEX-treated patients may in part be due to the dampening effect of DEX on the inflammatory neutrophil response, which could prevent neutrophil plugs with NETS in the lungs and other inflamed organs of patients.

Keywords

Acknowledgement

This work was supported by Amsterdam University Medical Center, University of Amsterdam and by a grant from the Dutch Arthritis Society.

References

  1. Liu YC, Kuo RL, Shih SR. COVID-19: the first documented coronavirus pandemic in history. Biomed J 2020;43:328-333. https://doi.org/10.1016/j.bj.2020.04.007
  2. World Health Organization. WHO coronavirus (COVID-19) dashboard [Internet]. https://covid19.who.int/ [accessed on 26 January 2022]. 
  3. Li J, Huang DQ, Zou B, Yang H, Hui WZ, Rui F, Yee NT, Liu C, Nerurkar SN, Kai JC, et al. Epidemiology of COVID-19: a systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes. J Med Virol 2021;93:1449-1458. https://doi.org/10.1002/jmv.26424
  4. Yang AP, Liu JP, Tao WQ, Li HM. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol 2020;84:106504.
  5. Vanderbeke L, Van Mol P, Van Herck Y, De Smet F, Humblet-Baron S, Martinod K, Antoranz A, Arijs I, Boeckx B, Bosisio FM, et al. Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity. Nat Commun 2021;12:4117.
  6. Schurink B, Roos E, Radonic T, Barbe E, Bouman CS, de Boer HH, de Bree GJ, Bulle EB, Aronica EM, Florquin S, et al. Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study. Lancet Microbe 2020;1:e290-e299. https://doi.org/10.1016/S2666-5247(20)30144-0
  7. Ouwendijk WJ, Raadsen MP, van Kampen JJ, Verdijk RM, von der Thusen JH, Guo L, Hoek RA, van den Akker JP, Endeman H, Langerak T, et al. High levels of neutrophil extracellular traps persist in the lower respiratory tract of critically ill patients with coronavirus disease 2019. J Infect Dis 2021;223:1512-1521. https://doi.org/10.1093/infdis/jiab050
  8. Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature 2020;582:469.
  9. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, et al. dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384:693-704. https://doi.org/10.1056/NEJMoa2021436
  10. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines [Internet]. Available at https://www.covid19treatmentguidelines.nih.gov/ [accessed on 3 November 3, 2021]. 
  11. Plumb J, Gaffey K, Kane B, Malia-Milanes B, Shah R, Bentley A, Ray D, Singh D. Reduced glucocorticoid receptor expression and function in airway neutrophils. Int Immunopharmacol 2012;12:26-33. https://doi.org/10.1016/j.intimp.2011.10.006
  12. Wang M, Gao P, Wu X, Chen Y, Feng Y, Yang Q, Xu Y, Zhao J, Xie J. Impaired anti-inflammatory action of glucocorticoid in neutrophil from patients with steroid-resistant asthma. Respir Res 2016;17:153.
  13. Martineau AR, Forouhi NG. Vitamin D for COVID-19: a case to answer? Lancet Diabetes Endocrinol 2020;8:735-736. https://doi.org/10.1016/S2213-8587(20)30268-0
  14. Sarohan AR. COVID-19: endogenous retinoic acid theory and retinoic acid depletion syndrome. Med Hypotheses 2020;144:110250.
  15. Midha IK, Kumar N, Kumar A, Madan T. Mega doses of retinol: a possible immunomodulation in Covid-19 illness in resource-limited settings. Rev Med Virol 2020;2:e2204.
  16. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 2002;3:499.
  17. Mol S, Hafkamp FM, Varela L, Simkhada N, Taanman-Kueter EW, Tas SW, Wauben MH, Groot Kormelink T, de Jong EC. Efficient neutrophil activation requires two simultaneous activating stimuli. Int J Mol Sci 2021;22:10106.
  18. Gupta S, Chan DW, Zaal KJ, Kaplan MJ. A high-throughput real-time imaging technique to quantify NETosis and distinguish mechanisms of cell death in human neutrophils. J Immunol 2018;200:869-879. https://doi.org/10.4049/jimmunol.1700905
  19. Parackova Z, Zentsova I, Bloomfield M, Vrabcova P, Smetanova J, Klocperk A, Meseznikov G, Casas Mendez LF, Vymazal T, Sediva A. Disharmonic inflammatory signatures in COVID-19: augmented neutrophils' but impaired monocytes' and dendritic cells' responsiveness. Cells 2020;9:2206.
  20. Lacy P. Mechanisms of degranulation in neutrophils. Allergy Asthma Clin Immunol 2006;2:98-108. https://doi.org/10.1186/1710-1492-2-3-98
  21. Borregaard N, Sorensen OE, Theilgaard-Monch K. Neutrophil granules: a library of innate immunity proteins. Trends Immunol 2007;28:340-345. https://doi.org/10.1016/j.it.2007.06.002
  22. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012;30:459-489. https://doi.org/10.1146/annurev-immunol-020711-074942
  23. Wang Y, Wu J, Newton R, Bahaie NS, Long C, Walcheck B. ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils. Biochim Biophys Acta 2013;1833:680-685. https://doi.org/10.1016/j.bbamcr.2012.11.027
  24. Souwer Y, Groot Kormelink T, Taanman-Kueter EW, Muller FJ, van Capel TM, Varga DV, Bar-Ephraim YE, Teunissen MB, van Ham SM, Kuijpers TW, et al. Human TH17 cell development requires processing of dendritic cell-derived CXCL8 by neutrophil elastase. J Allergy Clin Immunol 2018;141:2286-2289.e5. https://doi.org/10.1016/j.jaci.2018.01.003
  25. Smart SJ, Casale TB. TNF-alpha-induced transendothelial neutrophil migration is IL-8 dependent. Am J Physiol 1994;266:L238-L245. https://doi.org/10.1152/ajplung.1994.266.3.L238
  26. Dai X, Yamasaki K, Shirakata Y, Sayama K, Hashimoto K. All-trans-retinoic acid induces interleukin-8 via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes. J Invest Dermatol 2004;123:1078-1085. https://doi.org/10.1111/j.0022-202X.2004.23503.x
  27. Mukaida N, Okamoto S, Ishikawa Y, Matsushima K. Molecular mechanism of interleukin-8 gene expression. J Leukoc Biol 1994;56:554-558. https://doi.org/10.1002/jlb.56.5.554
  28. Vancurova I, Bellani P, Davidson D. Activation of nuclear factor-kappaB and its suppression by dexamethasone in polymorphonuclear leukocytes: newborn versus adult. Pediatr Res 2001;49:257-262. https://doi.org/10.1203/00006450-200102000-00021
  29. Nguyen GT, Green ER, Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance. Front Cell Infect Microbiol 2017;7:373.
  30. Laforge M, Elbim C, Frere C, Hemadi M, Massaad C, Nuss P, Benoliel JJ, Becker C. Tissue damage from neutrophil-induced oxidative stress in COVID-19. Nat Rev Immunol 2020;20:515-516. https://doi.org/10.1038/s41577-020-0407-1
  31. Dandona P, Mohanty P, Hamouda W, Aljada A, Kumbkarni Y, Garg R. Effect of dexamethasone on reactive oxygen species generation by leukocytes and plasma interleukin-10 concentrations: a pharmacodynamic study. Clin Pharmacol Ther 1999;66:58-65. https://doi.org/10.1016/S0009-9236(99)70054-8
  32. Shrestha S, Kim SY, Yun YJ, Kim JK, Lee JM, Shin M, Song DK, Hong CW. Retinoic acid induces hypersegmentation and enhances cytotoxicity of neutrophils against cancer cells. Immunol Lett 2017;182:24-29. https://doi.org/10.1016/j.imlet.2017.01.001
  33. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532-1535. https://doi.org/10.1126/science.1092385
  34. Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M, et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 2011;187:538-552. https://doi.org/10.4049/jimmunol.1100450
  35. Kruger P, Saffarzadeh M, Weber AN, Rieber N, Radsak M, von Bernuth H, Benarafa C, Roos D, Skokowa J, Hartl D. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog 2015;11:e1004651.
  36. Gillot C, Favresse J, Mullier F, Lecompte T, Dogne JM, Douxfils J. NETosis and the immune system in COVID-19: mechanisms and potential treatments. Front Pharmacol 2021;12:708302.
  37. Wan T, Zhao Y, Fan F, Hu R, Jin X. Dexamethasone inhibits S. aureus-induced neutrophil extracellular pathogen-killing mechanism, possibly through toll-like receptor regulation. Front Immunol 2017;8:60.
  38. Lapponi MJ, Carestia A, Landoni VI, Rivadeneyra L, Etulain J, Negrotto S, Pozner RG, Schattner M. Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. J Pharmacol Exp Ther 2013;345:430-437. https://doi.org/10.1124/jpet.112.202879
  39. Lewis HD, Liddle J, Coote JE, Atkinson SJ, Barker MD, Bax BD, Bicker KL, Bingham RP, Campbell M, Chen YH, et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol 2015;11:189-191. https://doi.org/10.1038/nchembio.1735
  40. Makrygiannakis D, Revu S, Engstrom M, af Klint E, Nicholas AP, Pruijn GJ, Catrina AI. Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis. Arthritis Res Ther 2012;14:R20.
  41. Song G, Shi L, Guo Y, Yu L, Wang L, Zhang X, Li L, Han Y, Ren X, Guo Q, et al. A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells. Oncotarget 2016;7:3144-3157. https://doi.org/10.18632/oncotarget.6551
  42. Hirsch D, Archer FE, Joshi-Kale M, Vetrano AM, Weinberger B. Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils. Mediators Inflamm 2011;2011:598345.
  43. Hafkamp FM, Groot Kormelink T, de Jong EC. Targeting DCs for tolerance induction: don't lose sight of the neutrophils. Front Immunol 2021;12:732992.
  44. Metzemaekers M, Cambier S, Blanter M, Vandooren J, de Carvalho AC, Malengier-Devlies B, Vanderbeke L, Jacobs C, Coenen S, Martens E, et al. Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019. Clin Transl Immunology 2021;10:e1271.
  45. Youn YJ, Lee YB, Kim SH, Jin HK, Bae JS, Hong CW. Nucleocapsid and spike proteins of SARS-CoV-2 drive neutrophil extracellular trap formation. Immune Netw 2021;21:e16.
  46. Janke M, Poth J, Wimmenauer V, Giese T, Coch C, Barchet W, Schlee M, Hartmann G. Selective and direct activation of human neutrophils but not eosinophils by Toll-like receptor 8. J Allergy Clin Immunol 2009;123:1026-1033. https://doi.org/10.1016/j.jaci.2009.02.015
  47. Aarts CE, Downes K, Hoogendijk AJ, Sprenkeler EG, Gazendam RP, Favier R, Favier M, Tool AT, van Hamme JL, Kostadima MA, et al. Neutrophil specific granule and NETosis defects in gray platelet syndrome. Blood Adv 2021;5:549-564. https://doi.org/10.1182/bloodadvances.2020002442
  48. Jauregui-Amezaga A, Cabezon R, Ramirez-Morros A, Espana C, Rimola J, Bru C, Pino-Donnay S, Gallego M, Masamunt MC, Ordas I, et al. Intraperitoneal administration of autologous tolerogenic dendritic cells for refractory Crohn's disease: a phase I study. J Crohn's Colitis 2015;9:1071-1078. https://doi.org/10.1093/ecco-jcc/jjv144