Skip to main content
Top
Published in: Clinical Reviews in Allergy & Immunology 2/2021

01-10-2021

A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics

Authors: Victoria Mutua, Laurel J. Gershwin

Published in: Clinical Reviews in Allergy & Immunology | Issue 2/2021

Login to get access

Abstract

Activated neutrophils release neutrophil extracellular traps (NETs) in response to a variety of stimuli. NETosis is driven by protein-arginine deiminase type 4, with the release of intracellular granule components that function by capturing and destroying microbes, including viral, fungal, bacterial, and protozoal pathogens. The positive effects of pathogen control are countered by pro-inflammatory effects as demonstrated in a variety of diseases. Components of NETS are non-specific, and other than controlling microbes, they cause injury to surrounding tissue by themselves or by increasing the pro-inflammatory response. NETs can play a role in enhancement of the inflammation seen in autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosis. In addition, autoinflammatory diseases such as gout have been associated with NETosis. Inhibition of NETs may decrease the severity of many diseases improving survival. Herein, we describe NETosis in different diseases focusing on the detrimental effect of NETs and outline possible therapeutics that can be used to mitigate netosis. There is a need for more studies and clinical trials on these and other compounds that could prevent or destroy NETs, thereby decreasing damage to patients.
Literature
5.
go back to reference Scapini P, Cassatella MA (2014) Social networking of human neutrophils within the immune system. Blood 124:710–719PubMedCrossRef Scapini P, Cassatella MA (2014) Social networking of human neutrophils within the immune system. Blood 124:710–719PubMedCrossRef
7.
go back to reference Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531PubMedCrossRef Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531PubMedCrossRef
11.
30.
go back to reference Delgado-Rizo V, Martínez-Guzmán MA, Iñiguez-Gutierrez L et al (2017) Neutrophil extracellular traps and its implications in inflammation: an overview. Front Immunol 8:81PubMedPubMedCentralCrossRef Delgado-Rizo V, Martínez-Guzmán MA, Iñiguez-Gutierrez L et al (2017) Neutrophil extracellular traps and its implications in inflammation: an overview. Front Immunol 8:81PubMedPubMedCentralCrossRef
31.
45.
47.
go back to reference Snoderly HT, Boone BA, Bennewitz MF (2019) Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment. Breast Cancer Res 21:1–13CrossRef Snoderly HT, Boone BA, Bennewitz MF (2019) Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment. Breast Cancer Res 21:1–13CrossRef
54.
go back to reference Akgul C, Moulding DA, Edwards SW (2001) Molecular control of neutrophil apoptosis. FEBS Lett 487:318–322PubMedCrossRef Akgul C, Moulding DA, Edwards SW (2001) Molecular control of neutrophil apoptosis. FEBS Lett 487:318–322PubMedCrossRef
60.
go back to reference Hoffmann JHO, Enk AH (2016) Neutrophil extracellular traps in dermatology: caught in the NET. J Dermatol Sci 84:3–10PubMedCrossRef Hoffmann JHO, Enk AH (2016) Neutrophil extracellular traps in dermatology: caught in the NET. J Dermatol Sci 84:3–10PubMedCrossRef
61.
go back to reference Engler D, Chezuba HP, Masuku P (2017) Psoriasis. SA Pharm J 84:38–42 Engler D, Chezuba HP, Masuku P (2017) Psoriasis. SA Pharm J 84:38–42
62.
go back to reference Lowes MA, Bowcock AM, Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445:866–873PubMedCrossRef Lowes MA, Bowcock AM, Krueger JG (2007) Pathogenesis and therapy of psoriasis. Nature 445:866–873PubMedCrossRef
64.
go back to reference Pinegin B, Vorobjeva N, Pinegin V (2015) Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity. Autoimmun Rev 14:633–640PubMedCrossRef Pinegin B, Vorobjeva N, Pinegin V (2015) Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity. Autoimmun Rev 14:633–640PubMedCrossRef
65.
go back to reference Witko-Sarsat V, Pederzoli-Ribeil M, Hirsh E et al (2011) Regulating neutrophil apoptosis: new players enter the game. Trends Immunol 32:117–124PubMedCrossRef Witko-Sarsat V, Pederzoli-Ribeil M, Hirsh E et al (2011) Regulating neutrophil apoptosis: new players enter the game. Trends Immunol 32:117–124PubMedCrossRef
68.
go back to reference Pan L, Lu MP, Wang JH et al (2020) Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr 16:19–30PubMedCrossRef Pan L, Lu MP, Wang JH et al (2020) Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr 16:19–30PubMedCrossRef
74.
go back to reference Apel F, Zychlinsky A, Kenny EF (2018) The role of neutrophil extracellular traps in rheumatic diseases. Nat Rev Rheumatol 14:467–475PubMedCrossRef Apel F, Zychlinsky A, Kenny EF (2018) The role of neutrophil extracellular traps in rheumatic diseases. Nat Rev Rheumatol 14:467–475PubMedCrossRef
75.
go back to reference Wigerblad G, Kaplan MJ (2020) NETs spread ever wider in rheumatic diseases. Nat Rev Rheumatol 16:73–74PubMedCrossRef Wigerblad G, Kaplan MJ (2020) NETs spread ever wider in rheumatic diseases. Nat Rev Rheumatol 16:73–74PubMedCrossRef
76.
go back to reference Herold KC, Vignali DAA, Cooke A, Bluestone JA (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243–256PubMedPubMedCentralCrossRef Herold KC, Vignali DAA, Cooke A, Bluestone JA (2013) Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol 13:243–256PubMedPubMedCentralCrossRef
77.
go back to reference Berezin A (2019) Neutrophil extracellular traps: the core player in vascular complications of diabetes mellitus. Diabetes Metab Syndr Clin Res Rev 13:3017–3023CrossRef Berezin A (2019) Neutrophil extracellular traps: the core player in vascular complications of diabetes mellitus. Diabetes Metab Syndr Clin Res Rev 13:3017–3023CrossRef
85.
go back to reference Desai J, Steiger S, Anders HJ (2017) Molecular pathophysiology of gout. Trends Mol Med Desai J, Steiger S, Anders HJ (2017) Molecular pathophysiology of gout. Trends Mol Med
89.
go back to reference Parkes G, Clare S, Goulding D et al (2006) Neutrophil activation and neutrophil extracellular trap formation in inflammatory bowel disease. Gastroenterology 130:A235 Parkes G, Clare S, Goulding D et al (2006) Neutrophil activation and neutrophil extracellular trap formation in inflammatory bowel disease. Gastroenterology 130:A235
92.
go back to reference Wärnberg J, Marcos A (2008) Low-grade inflammation and the metabolic syndrome in children and adolescents. Curr Opin Lipidol 19:11–15PubMedCrossRef Wärnberg J, Marcos A (2008) Low-grade inflammation and the metabolic syndrome in children and adolescents. Curr Opin Lipidol 19:11–15PubMedCrossRef
95.
go back to reference Frühbeck G (2004) The adipose tissue as a source of vasoactive factors. Curr Med Chem Cardiovasc Hematol Agents 2:197–208PubMedCrossRef Frühbeck G (2004) The adipose tissue as a source of vasoactive factors. Curr Med Chem Cardiovasc Hematol Agents 2:197–208PubMedCrossRef
104.
go back to reference Offermanns S (2006) Activation of platelet function through G protein-coupled receptors. Circ Res 99:1293–1304PubMedCrossRef Offermanns S (2006) Activation of platelet function through G protein-coupled receptors. Circ Res 99:1293–1304PubMedCrossRef
112.
go back to reference Liberman AC, Druker J, Refojo D, Arzt E (2008) Molecular mechanisms of action of some immunosuppressive drugs. Medicina 68:455–464 Liberman AC, Druker J, Refojo D, Arzt E (2008) Molecular mechanisms of action of some immunosuppressive drugs. Medicina 68:455–464
120.
go back to reference Stadler SC, Vincent CT, Fedorov VD et al (2013) Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelialto-mesenchymal transition in breast cancer cells. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1308362110 Stadler SC, Vincent CT, Fedorov VD et al (2013) Dysregulation of PAD4-mediated citrullination of nuclear GSK3β activates TGF-β signaling and induces epithelialto-mesenchymal transition in breast cancer cells. Proc Natl Acad Sci U S A. https://​doi.​org/​10.​1073/​pnas.​1308362110
123.
go back to reference Gad SE (2014) Prostaglandins. In: Encyclopedia of toxicology, third edn Gad SE (2014) Prostaglandins. In: Encyclopedia of toxicology, third edn
132.
go back to reference Tauber SC, Nau R (2008) Immunomodulatory properties of antibiotics. Curr Mol Pharmacol 1:68–79 Tauber SC, Nau R (2008) Immunomodulatory properties of antibiotics. Curr Mol Pharmacol 1:68–79
135.
go back to reference Gando S (2010) Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med Gando S (2010) Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med
137.
go back to reference Nguyen D, Coull BM (2017) Thrombosis. In: Primer on cerebrovascular diseases, second edn Nguyen D, Coull BM (2017) Thrombosis. In: Primer on cerebrovascular diseases, second edn
145.
go back to reference Skene PJ, Henikoff S (2013) Histone variants in pluripotency and disease. Development Skene PJ, Henikoff S (2013) Histone variants in pluripotency and disease. Development
146.
go back to reference Arrowsmith CH, Bountra C, Fish PV et al (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov Arrowsmith CH, Bountra C, Fish PV et al (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov
147.
go back to reference Chen R, Kang R, Fan XG, Tang D (2014) Release and activity of histone in diseases. Cell Death Dis Chen R, Kang R, Fan XG, Tang D (2014) Release and activity of histone in diseases. Cell Death Dis
150.
go back to reference Sanchez J (2017) Low molecular weight heparins—a new tool to disetangle from the NETs. Pharmacol Res 123:157PubMedCrossRef Sanchez J (2017) Low molecular weight heparins—a new tool to disetangle from the NETs. Pharmacol Res 123:157PubMedCrossRef
168.
go back to reference Singer M, Jones AM (2010) Bench-to-bedside review: the role of C1-esterase inhibitor in sepsis and other critical illnesses. Crit Care 15:203CrossRef Singer M, Jones AM (2010) Bench-to-bedside review: the role of C1-esterase inhibitor in sepsis and other critical illnesses. Crit Care 15:203CrossRef
171.
go back to reference Caliezi C, Wuillemin WA, Zeerleder S et al (2000) C1-esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev 52:91–112PubMed Caliezi C, Wuillemin WA, Zeerleder S et al (2000) C1-esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev 52:91–112PubMed
172.
174.
go back to reference Campbell JM (2019) Metformin. In: Encyclopedia of biomedical gerontology Campbell JM (2019) Metformin. In: Encyclopedia of biomedical gerontology
184.
go back to reference Amin M, Pushpakumar S, Muradashvili N et al (2016) Regulation and involvement of matrix metalloproteinases in vascular diseases. Front Biosci Landmark 21:89–118CrossRef Amin M, Pushpakumar S, Muradashvili N et al (2016) Regulation and involvement of matrix metalloproteinases in vascular diseases. Front Biosci Landmark 21:89–118CrossRef
200.
go back to reference Sharma P, Garg N, Sharma A et al (2019) Nucleases of bacterial pathogens as virulence factors, therapeutic targets and diagnostic markers. Int J Med Microbiol 309:151354PubMedCrossRef Sharma P, Garg N, Sharma A et al (2019) Nucleases of bacterial pathogens as virulence factors, therapeutic targets and diagnostic markers. Int J Med Microbiol 309:151354PubMedCrossRef
201.
go back to reference Nishino T, Morikawa K (2002) Structure and function of nucleases in DNA repair: shape, grip and blade of the DNA scissors. Oncogene 21:9022–9032PubMedCrossRef Nishino T, Morikawa K (2002) Structure and function of nucleases in DNA repair: shape, grip and blade of the DNA scissors. Oncogene 21:9022–9032PubMedCrossRef
216.
go back to reference Soccol CR, de Souza Vandenberghe LP, Spier MR et al (2010) The potential of probiotics: a review. Food Technol Biotechnol 48:413–434 Soccol CR, de Souza Vandenberghe LP, Spier MR et al (2010) The potential of probiotics: a review. Food Technol Biotechnol 48:413–434
228.
go back to reference Flaumenhaft R (2003) Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol 23:1152–1160PubMedCrossRef Flaumenhaft R (2003) Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol 23:1152–1160PubMedCrossRef
229.
go back to reference Weber C (2005) Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 96:612–616PubMedCrossRef Weber C (2005) Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 96:612–616PubMedCrossRef
233.
go back to reference Schaible HG, Ebersberger A, Segond Von Banchet G (2002) Mechanisms of pain in arthritis. Ann N Y Acad Sci Schaible HG, Ebersberger A, Segond Von Banchet G (2002) Mechanisms of pain in arthritis. Ann N Y Acad Sci
234.
go back to reference Attur M, Krasnokutsky S, Statnikov A et al (2015) Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheum. https://doi.org/10.1002/art.39279 Attur M, Krasnokutsky S, Statnikov A et al (2015) Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheum. https://​doi.​org/​10.​1002/​art.​39279
236.
go back to reference Botto M, Kirschfink M, Macor P et al (2009) Complement in human diseases: lessons from complement deficiencies. Mol Immunol Botto M, Kirschfink M, Macor P et al (2009) Complement in human diseases: lessons from complement deficiencies. Mol Immunol
237.
go back to reference Klaska I, Nowak JZ (2007) The role of complement in physiology and pathology. Postepy Hig Med Dosw (Online) 61:167-77 Klaska I, Nowak JZ (2007) The role of complement in physiology and pathology. Postepy Hig Med Dosw (Online) 61:167-77
247.
go back to reference Acquisto NM (2014) Heparin. In: Encyclopedia of toxicology, third edn Acquisto NM (2014) Heparin. In: Encyclopedia of toxicology, third edn
254.
go back to reference Mayansky AN, Mayansky NA (2009) Late-acting cytokine HMGBI: mediatory functions and prospects for clinical application. Immunologiya 4:232–237 Mayansky AN, Mayansky NA (2009) Late-acting cytokine HMGBI: mediatory functions and prospects for clinical application. Immunologiya 4:232–237
257.
go back to reference Maugeri N, Campana L, Gavina M et al (2014) Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost. https://doi.org/10.1111/jth.12710 Maugeri N, Campana L, Gavina M et al (2014) Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost. https://​doi.​org/​10.​1111/​jth.​12710
261.
go back to reference Schrezenmeier E, Dörner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:155–166PubMedCrossRef Schrezenmeier E, Dörner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16:155–166PubMedCrossRef
264.
go back to reference Bourboulia D, Stetler-Stevenson WG (2010) Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 20:161–168PubMedPubMedCentralCrossRef Bourboulia D, Stetler-Stevenson WG (2010) Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 20:161–168PubMedPubMedCentralCrossRef
272.
go back to reference Handono K, Sidarta YO, Pradana BA et al (2016) Vitamin D prevents endothelial damage induced by increased neutrophil extracellular traps formation in patients with systemic lupus erythematosus. Acta Med Indones 46:189–198 Handono K, Sidarta YO, Pradana BA et al (2016) Vitamin D prevents endothelial damage induced by increased neutrophil extracellular traps formation in patients with systemic lupus erythematosus. Acta Med Indones 46:189–198
Metadata
Title
A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics
Authors
Victoria Mutua
Laurel J. Gershwin
Publication date
01-10-2021
Publisher
Springer US
Published in
Clinical Reviews in Allergy & Immunology / Issue 2/2021
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-020-08804-7

Other articles of this Issue 2/2021

Clinical Reviews in Allergy & Immunology 2/2021 Go to the issue