Table 2.

Overlapping and opposing effects of neutrophil-derived extracellular vesicles and NETs in health and disease. NETs and extracellular vesicles trigger a large variety of secondary effector mechanisms that are not entirely included in this table.

Biological Context	Neutrophil EVs	NETs	References
General	May act either as a pro-inflammatory or anti-inflammatory mediator depending on target cells and activation context	May act either as a pro-inflammatory or anti-inflammatory mediator depending on activation context	[87,88]
Complement	Activate complement	Activate complement	[60,89]
Erythrocytes	Bind erythrocytes in the presence of complement	Bind erythrocytes	[89,90]
Monocytes/Macrophages	May induce a pro- or anti-inflammatory response in monocytes/macrophages depending on stimulus	May induce a pro- or anti-inflammatory response in monocytes/macrophages	[26,72,91,92]
Neutrophils	May induce a pro- or anti-inflammatory response in neutrophils depending on stimulus	Pro-inflammatory, and anti-inflammatory in aggregated form	[26,93,94,95,96]
Blood platelets	Activate blood platelets via αMβ2-mediated binding	Activate blood platelets by histones	[97,98]
Endothelial cells	May induce a pro- or anti-inflammatory response in endothelial cells and may promote or reduce para-endothelial permeability depending on stimulus	Activate endothelial cells by Interleukin-1α and Cathepsin G and promote endothelial permeability	[26,99,100]
T-cells	May induce a pro- or anti-inflammatory response in T-cells	May induce a pro- or anti-inflammatory response in T-cells	[35,101,102]
Infection	Antibacterial by: -bacteria aggregation on surface -granule proteins	Antibacterial by: -bacteria entrapment -granule proteins -antimicrobial peptides -histones, DNA	[33,50,103,104]
	No direct evidence for antiviral activity	Antiviral by: -virus entrapment -granule proteins -antimicrobial peptides -histones, DNA	[105]
	Antifungal by granule proteins	Antifungal by calprotectin	[47,106]
	No direct evidence for antiparasitic activity	Antiparasitic by: -entrapment -killing	[107]
Non-autoimmune cardiovascular disease	Promote thrombosis by exposing tissue factor, platelet activating factor, and possibly phosphatidylserine	Promote thrombosis by exposing von Willebrand factor, histones, tissue factor, and phosphatidylserine	[98,103,108,109,110]
	Promote atherosclerosis by delivering microRNA (miR-155)	Promote atherosclerosis by macrophage activation possibly via granule enzymes	[56,111]
Cancer	Anti-tumorigenic by inducing apoptosis of cancer cells or pro-tumorigenic	Pro-tumorigenic, influencing growth, progression, and spreading of cancer by various mechanisms	[112,113,114]
	No direct evidence for cancer-associated pro- or anti-thrombotic effect	May promote cancer-associated thrombosis	[115]
Autoimmunity
ANCA-associated vasculitis	Promote thrombosis by exposing tissue factor; contains autoantigen; may trigger vasculitis	Promote thrombosis by exposing tissue factor; contains autoantigen; may trigger vasculitis	[66,116,117,118]
Psoriasis	May trigger inflammation	May trigger autoimmunity and inflammation by bound pro-inflammatory IL-17	[119,120]
Systemic lupus erythematosus (SLE)	No evidence for direct involvement in pathogenesis	Contain autoantigen and may contribute to pathogenesis	[121,122,123]
Rheumatoid arthritis (RA)	Protective effect on cartilage	Contain autoantigen and may contribute to pathogenesis of RA; damage cartilage by NE	[49,124,125]
Pulmonary disease	Contribute to disease pathology	Contribute to disease pathology	[85,126,127]