Table 1.

Neutrophil extracellular traps in host defense and disease.

Cell	Mechanism of ETs Formation	Stimulus/Models	Biological Effect Protective Deleterious
Neutrophil in Cancer	Suicidal (ROS-dependent) [91,107,108,109,110] Early/rapid ROS-independent (but may alternatively be dependent on autophagy) [111] Mitochondrial NETs [61]	In vivo Murine models of: breast cancer [91], lung carcinoma [107], metastatic colorectal cancer [109,110], lung carcinoma [108] Ex vivo Serum samples of patients with metastatic colorectal [109,110] and human tissue samples of breast cancer [91] In vitro Cancer cells [91], pancreatic cancer cells [111], anaplastic thyroid cancer cells [61]	Entrapment of tumor cells [107]	Association with an aggressive subtype of breast cancer [91] Tumor progression [61,110] Metastasis [91,107,108,109,110] Reduction in disease-free survival [109] Cancer-associated thrombosis [111]
Neutrophil in Central Nervous System Diseases	ROS-dependent [112] Nuclear DNA [113,114,115,116]	In vivo Murine model of Alzheimer’s disease, meningitis and [112,116] Piglet model of S. suis meningitis [113] In vitro Thrombi from patients with acute ischemic stroke [114,115]; paraffin sections of human cortex from Alzheimer’s disease brains [116] CSF of patients with S. pneumoniae meningitis [112] Modified human BCSFB model [113]	Entrapment of streptococci [113]	Alzheimer’s disease pathogenesis [116] Impairment of pneumococci clearance in meningitis [112] Poorer clinical outcomes and inflammation aggravation in patients with acute ischemic stroke [115]; Important constituents of cerebral thrombi [114]
Neutrophil in Pulmonary Diseases	Suicidal, ROS-dependent [117,118] ROS-dependent [119] Nuclear DNA [120,121,122]	In vivo Murine and human model of rhinovirus-induced allergic asthma exacerbation [122], murine model of S. pneumoniae induced pneumonia [119], and PTB [121] Ex vivo Human lung samples [121] In vitro Sputum samples of asthma patients/human airway epithelial cells [117] Sputum samples of COPD patients [118,120]		Asthma severity and exacerbation [117,122] Airway epithelial and endothelial damage [117] Severity of S. pneumoniae induced pneumonia [119] COPD severity and airway flow limitation [118,120] PTB pathogenesis and severity [121]
Neutrophil in Autoimmune Diseases	ROS-dependent [123] Mitochondrial NETs (mtDNA, mtROS) [25] Not described [15]	In vitro Immune complexes (Anti-LL-37, anti-HNP, PR3 and MPO, ANCAs) [123] Healthy and lupus neutrophils (PMA and immune complexes) [25] Healthy and rheumatoid arthritis neutrophils (PMA and A23187) [15]		Autoimmune diseases (systemic lupus erythematosus, psoriasis, vasculitis, rheumatoid arthritis) [15,25,123,124]
Neutrophil in Thrombosis/Cardiovascular Disorders	Nuclear DNA [125] ROS-dependent [126]	In vitro Blood neutrophils and platelets [125] In vivo Deep vein thrombosis model (Baboons) [125] In vivo Murine model (cholesterol crystals) [126]		Thrombosis [125] Atherosclerosis [126]
Neutrophil and Virus	ROS-dependent [127,128] Suicidal, ROS-dependent [92] PAD-4 dependent [94] Suicidal, presence of Cit-H3 and MPO-DNA complexes [94,95,96,97,98,99]	In vivo Murine model of influenza A virus H1N1pneumonia [127] and Chikungunya virus infection [128] In vitro Neutrophils + influenza virus–primed epithelial cells [127] Serum samples and/or nasal swab specimens from COVID-19 patients [92,93,94,95,96,97,98,99] Neutrophils + SARS-CoV-2 [92,94] Neutrophils + Chikungunya virus [128] Ex vivo BALF and lung autopsies from COVID-19 patients [94,95,96]	Virus capture, Neutralization and reduction of viral load in the blood. [128]	Lung injury [127] Thrombosis formation in COVID-19 [92,96,99] COVID-19 Pneumonia [97] COVID-19 severity and vascular damage [94,95,98,99]
Neutrophil and Fungi	Suicidal, ROS-dependent [66,129,130] Vital NETs, ROS-independent [65] Not described [30]	In vivo Murine model of A. fumigatus [66] Murine model of C. albicans infection [129] In vitro A fumigatus conidia [130] C. albicans (β-glucan) [65] Ex vivo Active sporotrichosis lesion [30]	Entrapment of conidia, the only fungistatic effect [66,130] Capture and kill C. albicans yeast and hyphal forms [65,129] Antimicrobial effect [30]
Neutrophil and Protozoa	Early/rapid, ROS-independent, and late ROS-dependent [68] Suicidal, ROS-dependent [64] ROS-dependent [28,73,131] ROS-independent [132] Not described [27,29,67]	In vivo Murine model of T. cruzi [131] Murine model of Malaria with P. berghei [132] and P. chabaudi [73] Murine model of T. gondii [28] Ex vivo ATL active cutaneous lesions [29] In vitro Leishmania spp.—amastigotes, promastigote/lipophosphoglycan [64,67,68] T. cruzi [131] Blood samples from patients infected with P. falciparum [73,132]	Containment of promastigotes at the inoculation site and Leishmania killing [64,68] Limits infection by affecting the parasite’s pathogenicity [131] Antimicrobial effect [29,73,132] Interferes with the parasite’s ability to invade cells [28]	Activation of emergency granulopoiesis via GM-CSF production, and induction of the endothelial cytoadhesion receptor ICAM-1 [73] Stimulus of ANA production, which may lead to autoimmunity [27]

ETs, extracellular traps; ROS, reactive oxygen species; NETs, neutrophil extracellular traps; CSF, cerebrospinal fluid; BCSFB, blood-cerebrospinal fluid barrier; PTB, pulmonary tuberculosis; COPD, chronic obstructive pulmonary disease; mtDNA, mitochondrial DNA; GM-CSF, granulocyte macrophage colony-stimulating factor; CF5a, complement factor 5a; LPS, lipopolysaccharide; TLR4, toll like receptor 4; anti-LL-37, antimicrobial peptide, anti-HNP, human neutrophil peptide; PR3, proteinase-3; BALF, bronchoalveolar lavage fluid; Cit-H3, citrullinated histone H3; MPO, myeloperoxidase; ANCAs, anti-neutrophil cytoplasmic antibodies; PMA, phorbol-12-myristate-13-acetate; oxLDL, oxidized low-density lipoprotein; ICAM-1, intercellular Adhesion Molecule 1; ANA, antinuclear Antibodies; ATL, American Tegumentary Leishmaniasis.