SUMMARY
Extracellular vesicles (EVs) are membrane-derived vesicles that mediate intercellular communications. Neutrophils produce different subtypes of EVs during inflammatory responses. Neutrophil-derived trails (NDTRs) are generated by neutrophils migrating toward inflammatory foci, whereas neutrophil-derived microvesicles (NDMVs) are thought to be generated by neutrophils that have arrived at the inflammatory foci. However, the physical and functional characteristics of neutrophil-derived EVs are incompletely understood. In this study, we investigated the similarities and differences between neutrophil-derived EV subtypes. Neutrophil-derived EVs shared similar characteristics regarding stimulators, generation mechanisms, and surface marker expression. Both neutrophil-derived EV subtypes exhibited similar functions, such as direct bactericidal activity and induction of monocyte chemotaxis via MCP-1. However, NDTR generation was dependent on the integrin signaling, while NDMV generation was dependent on the PI3K pathway. The CD16 expression level differentiated the neutrophil-derived EV subtypes. Interestingly, both subtypes showed different patterns of miRNA expression and were easily phagocytosed by monocytes. NDTRs induced M1 macrophage polarization, whereas NDMVs induced M2 macrophage polarization. Moreover, NDTRs but not NDMVs exerted protective effects against sepsis-induced lethality in a murine sepsis model and pathological changes in a murine chronic colitis model. These results suggest a new insight into neutrophil-derived EV subtypes: proinflammatory NDTRs and anti-inflammatory NDMVs.
Key points
Neutrophil-derived trails are proinflammatory extracellular vesicles that induce M1 macrophage polarization and protect against inflammation
Neutrophil-derived microvesicles are anti-inflammatory extracellular vesicles that induce M2 macrophage polarization
Abbreviations
- EV
- extracellular vesicle
- NDMV
- neutrophil-derived microvesicles
- NDTR
- neutrophil-derived trails
- NK cells
- natural killer cells
- MoDCs
- monocyte-derived dendritic cells
- CXCL12
- CXC-chemokine ligand 12
- PAMPs
- pathogen-associated molecular patterns
- fMLP
- formyl-methionyl-leucyl-phenylalanine
- LPS
- lipopolysaccharide
- E. coli
- Escherichia coli
- S. aureus
- Staphylococcus aureus
- DAMPs
- danger-associated molecular patterns
- HMGB1
- high mobility group box 1
- TNF-α
- tumor necrosis factor-α
- IFN-γ
- interferon-γ
- TGF-β
- tumor growth factor-β
- IL-4
- interleukin-4
- L-NAME
- N(γ)-nitro-L-arginine methyl ester
- PMA
- phorbol 12-myristate 13-acetate
- MCP-1
- monocyte chemoattractant protein 1
- iNOS
- inducible nitric oxide synthase
