Neutrophil Extracellular Traps and By-Products Play a Key Role in COVID-19: Pathogenesis, Risk Factors, and Therapy
Abstract
:1. Introduction
2. Innate Immunity
3. NET Formation and Extracellular DNA/Nucleic Acids Release
3.1. NET Formation/General Function
3.2. Stimuli
3.3. Role of Platelets
4. NET Nucleotidic Components: Nucleosomes and Circulating Cell-Free DNA
4.1. Nuclear DNA
4.2. Mitochondrial DNA
4.3. RNA and Modified Nucleic Acids
4.4. DNA Re-Entry into Cell
5. NET and Extracellular DNA Release Function: A Double-Edged Sword
5.1. Beneficial Innate Response
5.2. Detrimental Innate Response
5.2.1. Sterile Diseases Induced by Unbalanced NET Formation
5.2.2. Autoimmune Diseases:
5.2.3. Intravascular Diseases:
5.2.4. Inflammatory Diseases:
5.2.5. Other Pathologies:
5.2.6. Conclusion on Sterile Diseases Associated With NETs Non-Balanced Formation and Degradation:
6. NETs and NETs By-Products: Viral Pathogenesis
7. Strategies in Targeting NET Formation and NETs By-Products
7.1. DNase1
7.2. Neutrophil Elastase
7.3. Other Strategies
8. Viral-Induced ARDS/Cytokine Storm
9. Proposed Mechanisms for the Role of NETs Formation in COVID-19
10. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
COVID-19 | Coronavirus 2019 disease |
NETs | neutrophil extracellular traps |
SARS CoV2 | severe acute respiratory syndrome-coronavirus 2 |
TLR | toll-like receptors |
CLEC | C-type lectin like receptors |
CDC | Center for Disease Control and Prevention |
WHO | World Health Organization |
ARDS | acute respiratory distress syndrome |
ALI | acute lung injury |
PAF | platelet activating factor |
IL-8 or CXCL8 | interleukin-8 |
LPS | lipopolysaccharide |
PKC | protein kinase C |
PMA | phorbol myristate acetate |
PAD4 | peptidyl arginine deiminase 4 |
MPO | myeloperoxidase |
NE | neutrophil elastase |
ETs | extracellular traps |
TNF α | tumor necrosis factor α |
Cit-H3 | citrullinated histone H3 |
SIRS | systemic inflammatory response syndrome |
WBC | white blood cells |
cirDNA | circulating DNA |
HMGB1 | high mobility group box-1 |
ROS | reactive oxygen species |
GM-CSF | colony-stimulating factor |
DAMPs | damage-associated molecular patterns |
PRR | pattern recognition receptors |
STING | stimulator of interferon genes |
pDCs | plasmacytoid dendritic cells |
ORF-9b | open reading frame 9b |
DRP1 | dynamin-related protein 1 |
iIFN | inducible interferon |
NLRP3 | NOD-, LRR- and pyrin domain-containing protein 3) |
NLRs | (NOD)-like receptors |
NOD | nucleotide-binding oligomerization domain |
DV | dengue virus |
RNA | ribonucleic acid |
ss-RNA | single-stranded RNA |
ICs | immune complexes |
PAMPs | pathogen-associated molecular patterns |
HIV | human immunodeficiency virus |
SLE | systemic lupus erythematosus |
RA | rheumatoid arthritis |
TMA | thrombotic microangiopathy |
CRP | C-reactive protein |
RSV | respiratory syncytial virus |
VHF | viral hemorrhagic fevers |
CHIKV | chikungunya virus |
SIV | simian immunodeficiency virus |
ENaC | epithelial sodium channel |
HCQ | Hydroxychloroquine |
IL-6 | interleukin 6 |
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Diseases | NET Dysregulation Associated Diseases | COVID-19 Comorbidities/Host Risk Factors |
---|---|---|
Non-autoimmune | Cerebrovascular disease * (McMichael et al. [31]) | |
Acute lung injury (Grommes et al. [32]) | Pulmonary diseases * (McMichael et al. [31]) | |
SIRS (Hamaguchi et al. [33]) | ||
Sepsis (Chen L et al. [34]) | Sepsis (Hirose et al. [9]) | |
Thrombosis (Frangou et al. [35]) | ||
Kidney diseases (Nakazawa et al. [21]) | Kidney diseases * (McMichael et al. [31]) | |
Obesity (D’abondanza et al. [36]) | Obesity * (McMichael et al. [31]) | |
Vasculitis (Kessenbrock et al. [37]) | ||
Sickle cell disease (Schimmel et al. [38]) | Sickle cell disease (Hussain et al. [39]) | |
heart failure (Bonaventura et al. [40]) | Cardiovascular disease * (McMichael et al. [31]) | |
Atherosclerosis (Doering et al. [41]) | ||
hypertension (Vijay et al. [42]) | Hypertension * (McMichael et al. [31]) | |
Disseminated intravascular coagulation (Tang et al. [43]) | Disseminated intravascular coagulation (Stiel et al. [5]) | |
Chronic inflammation disease (Tan et al. [24]) | Chronic inflammation disease (Yang et al. [44]) | |
Cystic fibrosis (Manzenreiter et al. [45]) | ||
TRALI (Caudriller et al. [14]) | ||
Periodontis (Lee and Lee, [46]) | ||
Pre-eclampsia (Moodley et al. [47]) | ||
Neuropathy (Takeuchi et al. [48]) | ||
Gouty arthritis (Chatfield et al. [49]) | ||
Felty syndrome (Dwivedi et al. [50]) | ||
Inflammatory bowel disease (Agelidou et al. [51]) | Inflammatory bowel disease (Danese et al. [52]) | |
Liver disease (Hilscher et al. [53]) | ||
Autoimmune | Anti-phospholipid syndrome (Lee et al. [54]) | |
Type 1 Diabetes (Menegonza et al. [55]) | Type 1 Diabetes (Yang et al. [44]) | |
Psoriasis (Lee et al. [54]) | ||
Rheumatoid arthritis (Rohrbach et al. [56]) | Rheumatoid arthritis (Favalli et al. [57]) | |
Lupus (SLE) (Lamphier et al. [28]; Boelz et al. [58]) |
Overall | Pathologies | Vascular and Coagulation Consequences | Biological Features |
---|---|---|---|
Complex disease | Respiratory failure | Disseminated intravascular coagulation | High level Neutrophils |
Inflammatory disease | ARDS | Endothelium damage | High level Interferon |
Multi-organ damage | Heart failure | Systemic vascular permeability | High level C reactive protein |
Acute cardiac injury | Prothrombotic | High level Lactate deshydrogenases | |
Vasculitis | Abnormality of coagulation function | High level proinflammatory cytokines | |
Type 1 Diabetes sensitization | Elevated presence of fibrinogen | ||
Kidney diseases | High level antiphospholipid antibodies | ||
Inflammatory bowel disease | |||
Chronic inflammation disease | |||
Sepsis | |||
Rheumatoid arthritis | |||
Neuropathy | |||
Gouty arthritis sensitization |
Main Drugs/Treatments | Biological Targets | Mode of Action | |
---|---|---|---|
COVID-19 | Convalescent plasma | virus | virus neutralization |
Monoclonal antibody | virus proteins | virus neutralization | |
anti-IL6 | IL-6 | immuno-modulation | |
IFNs | Immunological cells | antiviral proteins synthesis and immunological cell activation | |
Jakinib | Janus kinase | immuno-modulation | |
Remdesivir | RNA polymerase | inhibition of viral replication | |
Ribavirin | RNA polymerase | inhibition of viral replication | |
Sofosbuvir | RNA polymerase | inhibition of viral replication | |
Lopinavir/Ritonavir | 3-chymotrypsine like protease activity | inhibition of viral replication | |
Arbidol | virus/cell binding complex | virus penetration into cells | |
Camostat mesylate | S protein | virus penetration into cells | |
Hydroxychloroquine | ACE2 glycosylation and phagolysosomes | cell penetration and intracellular virus uncoating | |
Dexamethasone | Glucocorticoid receptor | anti-inflammatory | |
COVID-19 NETopathies | DNase1 | DNA | DNA degradation |
Silvelestat | Neutrophil elastase | antiprotease | |
Monoclonal antibodies | histones | histone blocking | |
Monoclonal antibodies | CLEC | inhibition of platelet activation | |
Monoclonal antibodies | TLR | inhibition of platelet activation | |
Monoclonal antibodies | IL-6 | inhibition of neutrophil function | |
Monoclonal antibodies | IL-1 | inhibition of neutrophil function | |
Monoclonal antibodies | IL-26 | inhibition of DNA self-entry | |
Anti-coagulant | Platelet/Neutrophil/NET complex | Inhibition of platelet activation | |
Hydroxychloroquine | NET | inhibition of NET stimulation | |
Metformin | Alarmin HMGB1 | NET clearance | |
Colchicin | Neutrophil | neutrophil recruitement |
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Thierry, A.R.; Roch, B. Neutrophil Extracellular Traps and By-Products Play a Key Role in COVID-19: Pathogenesis, Risk Factors, and Therapy. J. Clin. Med. 2020, 9, 2942. https://doi.org/10.3390/jcm9092942
Thierry AR, Roch B. Neutrophil Extracellular Traps and By-Products Play a Key Role in COVID-19: Pathogenesis, Risk Factors, and Therapy. Journal of Clinical Medicine. 2020; 9(9):2942. https://doi.org/10.3390/jcm9092942
Chicago/Turabian StyleThierry, Alain R., and Benoit Roch. 2020. "Neutrophil Extracellular Traps and By-Products Play a Key Role in COVID-19: Pathogenesis, Risk Factors, and Therapy" Journal of Clinical Medicine 9, no. 9: 2942. https://doi.org/10.3390/jcm9092942