Dexamethasone, but Not Vitamin D or A, Dampens the Inflammatory Neutrophil Response to Protect At-risk COVID-19 Patients
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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.
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.
참고문헌 (48)
- Liu YC, "COVID-19 : the first documented coronavirus pandemic in history", Biomed J, 43, pp.328~333 (2020)
- "WHO coronavirus (COVID-19) dashboard"[URL]
- Li J, "Epidemiology of COVID-19 : a systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes", J Med Virol, 93, pp.1449~1458 (2021)
- Yang AP, "The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19patients", Int Immunopharmacol, 84, pp.106504~ (2020)
- Vanderbeke L, "Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity", Nat Commun, 12, pp.4117~ (2021)
- Schurink B, "Viral presence and immunopathology in patients with lethal COVID-19 : a prospective autopsy cohort study", Lancet Microbe, 1, pp.e290~e299 (2020)
- Ouwendijk WJ, "High levels of neutrophil extracellular traps persist in the lower respiratory tract of critically ill patients with coronavirus disease 2019", J Infect Dis, 223, pp.1512~1521 (2021)
- Ledford H, "Coronavirus breakthrough : dexamethasone is first drug shown to save lives", Nature, 582, pp.469~ (2020)
- Horby P, "dexamethasone in hospitalized patients with Covid-19", N Engl J Med, 384, pp.693~704 (2021)
- "Coronavirus disease 2019 (COVID-19) treatment guidelines"[URL]
- Plumb J, "Reduced glucocorticoid receptor expression and function in airway neutrophils", Int Immunopharmacol, 12, pp.26~33 (2012)
- Wang M, "Impaired anti-inflammatory action of glucocorticoid in neutrophil from patients with steroid-resistant asthma", Respir Res, 17, pp.153~ (2016)
- Martineau AR, "Vitamin D for COVID-19 : a case to answer", Lancet Diabetes Endocrinol, 8, pp.735~736 (2020)
- Sarohan AR, "COVID-19 : endogenous retinoic acid theory and retinoic acid depletion syndrome", Med Hypotheses, 144, pp.110250~ (2020)
- Midha IK, "Mega doses of retinol : a possible immunomodulation in Covid-19 illness in resource-limited settings", Rev Med Virol, 2, pp.e2204~ (2020)
- Jurk M, "Human TLR7 or TLR8independently confer responsiveness to the antiviral compound R-848", Nat Immunol, 3, pp.499~ (2002)
- Mol S, "Efficient neutrophil activation requires two simultaneous activating stimuli", Int J Mol Sci, 22, pp.10106~ (2021)
- Gupta S, "A high-throughput real-time imaging technique to quantify NETosis and distinguish mechanisms of cell death in human neutrophils", J Immunol, 200, pp.869~879 (2018)
- Parackova Z, "Disharmonic inflammatory signatures in COVID-19 : augmented neutrophils’ but impaired monocytes’ and dendritic cells’ responsiveness", Cells, 9, pp.2206~ (2020)
- Lacy P, "Mechanisms of degranulation in neutrophils", Allergy Asthma Clin Immunol, 2, pp.98~108 (2006)
- Borregaard N, "Neutrophil granules : a library of innate immunity proteins", Trends Immunol, 28, pp.340~345 (2007)
- Amulic B, "Neutrophil function : from mechanisms to disease", Annu Rev Immunol, 30, pp.459~489 (2012)
- Wang Y, "ADAM17 cleaves CD16b(FcγRIIIb)in human neutrophils", Biochim Biophys Acta, 1833, pp.680~685 (2013)
- Souwer Y, "Human TH17 cell development requires processing of dendritic cell-derived CXCL8 by neutrophil elastase", J Allergy Clin Immunol, 141, pp.2286~2289 (2018)
- Smart SJ, "TNF-alpha-induced transendothelial neutrophil migration is IL-8 dependent", Am J Physiol, 266, pp.L238~L245 (1994)
- Dai X, "All-trans-retinoic acid induces interleukin-8via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes", J Invest Dermatol, 123, pp.1078~1085 (2004)
- Mukaida N, "Molecular mechanism of interleukin-8 gene expression", J Leukoc Biol, 56, pp.554~558 (1994)
- Vancurova I, "Activation of nuclear factor-kappaB and its suppression by dexamethasone in polymorphonuclear leukocytes : newborn versus adult", Pediatr Res, 49, pp.257~262 (2001)
- Nguyen GT, "Neutrophils to the ROScue : Mechanisms of NADPH oxidase activation and bacterial resistance", Front Cell Infect Microbiol, 7, pp.373~ (2017)
- Laforge M, "Tissue damage from neutrophil-induced oxidative stress in COVID-19", Nat Rev Immunol, 20, pp.515~516 (2020)
- Dandona P, "Effect of dexamethasone on reactive oxygen species generation by leukocytes and plasma interleukin-10 concentrations : a pharmacodynamic study", Clin Pharmacol Ther, 66, pp.58~65 (1999)
- Shrestha S, "Retinoic acid induces hypersegmentation and enhances cytotoxicity of neutrophils against cancer cells", Immunol Lett, 182, pp.24~29 (2017)
- Brinkmann V, "Neutrophil extracellular traps kill bacteria", Science, 303, pp.1532~1535 (2004)
- Villanueva E, "Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus", J Immunol, 187, pp.538~552 (2011)
- Kruger P, "Neutrophils : between host defence, immune modulation, and tissue injury", PLoS Pathog, 11, pp.e1004651~ (2015)
- Gillot C, "NETosis and the immune system in COVID-19 : mechanisms and potential treatments", Front Pharmacol, 12, pp.708302~ (2021)
- Wan T, "Dexamethasone inhibits S. aureus-induced neutrophil extracellular pathogen-killing mechanism, possibly through toll-like receptor regulation", Front Immunol, 8, pp.60~ (2017)
- Lapponi MJ, "Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs", J Pharmacol Exp Ther, 345, pp.430~437 (2013)
- Lewis HD, "Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation", Nat Chem Biol, 11, pp.189~191 (2015)
- Makrygiannakis D, "Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis", Arthritis Res Ther, 14, pp.R20~ (2012)
- Song G, "A novel PAD4", SOX4, Oncotarget, pp.2016, 7[DOI]
- Hirsch D, "Decreased anti-inflammatory responses to vitamin D in neonatal neutrophils", Mediators Inflamm, 2011, pp.598345~ (2011)
- Hafkamp FM, "Targeting DCs for tolerance induction : don’t lose sight of the neutrophils", Front Immunol, 12, pp.732992~ (2021)
- Metzemaekers M, "Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019", Clin Transl Immunology, 10, pp.e1271~ (2019)
- 윤영진, "Nucleocapsid and Spike Proteins of SARS-CoV-2 Drive Neutrophil Extracellular Trap Formation", Immune Network, 21(2), pp.1~8 (2021), 대한면역학회[DOI]
- Janke M, "Selective and direct activation of human neutrophils but not eosinophils by Toll-like receptor 8", J Allergy Clin Immunol, 123, pp.1026~1033 (2009)
- Aarts CE, "Neutrophil specific granule and NETosis defects in gray platelet syndrome", Blood Adv, 5, pp.549~564 (2021)
- Jauregui-Amezaga A, "Intraperitoneal administration of autologous tolerogenic dendritic cells for refractory Crohn’s disease : a phase I study", J Crohn’s Colitis, 9, pp.1071~1078 (2015)
