Neutrophil-derived extracellular vesicles modulate the phenotype of naïve human neutrophils

Abstract

Neutrophils (PMN) regulate inflammation in many ways, including communication with other immune cells via extracellular vesicles (EVs). EVs released by human neutrophils activated with N‐formylmethionyl‐leucyl‐phenylalanine (fMLF) (PMN‐fMLF EVs) had an outside‐out orientation and contained functionally important neutrophil plasma membrane proteins, including flavocytochrome b558, and enzymatically active granule proteins, elastase, and myeloperoxidase. Treatment of naïve PMN with PMN‐fMLF EVs primed fMLF‐stimulated NADPH oxidase activity, increased surface expression of the complement receptors CD11b/CD18 and CD35, the specific granule membrane protein CD66, and flavocytochrome b558, and promoted phagocytosis of serum‐opsonized Staphylococcus aureus. The primed oxidase activity reflected increased surface expression of flavocytochrome b558 and phosphorylation of SER345 in p47phox, two recognized mechanisms for oxidase priming. Taken together, these data demonstrate that stimulated PMN released EVs that altered the phenotype of naïve phagocytes by priming of the NADPH oxidase activity and augmenting phagocytosis, two responses that are integral to optimal PMN host defense.

Neutrophil Extracellular Vesicles: A Delicate Balance between Pro-Inflammatory Responses and Anti-Inflammatory Therapies

“…The critical role of nEVs on naïve neutrophils may explain how acute local inflammation in a limited area can expand and become chronic. This point is illustrated by the recent work of Nauseef’s group [ 79 ], which demonstrated that the treatment of naïve neutrophils with EVs derived from fMLF-stimulated neutrophils primed NADPH oxidase activity. This is reflected by an increase in ROS production in response to a suboptimal concentration of fMLF.…”

The roles of extracellular vesicles in the immune system

“…Stimulation of neutrophils by opsonized particles induces the release of bacteriostatic EVs, which form large aggregates with bacteria 82 . Furthermore, EVs from neutrophils stimulated with N -formylmethionyl-leucyl-phenylalanine, a chemotactic factor produced by bacteria, prime resting naive neutrophils for NADPH oxidase activity and enhance their phagocytic capacity 83 . Upon non-lytic NETosis, which involves the expulsion of nuclear chromatin and granules, anucleated, membrane-enclosed large remnants of neutrophils (cytoplasts) are left behind.…”

Neutrophil-derived extracellular vesicles promote feed-forward inflammasome signaling in cystic fibrosis airways

“…In fact, EVs can be generated from all of the cells present in the CF lung including, but not limited to the neutrophils and epithelial cells, such as macrophages, monocytes, T‐cells, as well as bacteria and fungus 42 . There have been recent studies that EVs from neutrophils can cause activation of other neutrophils, 43 and that EVs from S. aureus can down‐regulate the ability of neutrophils to kill bacterial pathogens 44 . EVs from CFTR‐mutated epithelial cells were able to activate neutrophils 45 and our study now documents communication in the other direction, that is, from neutrophils to epithelial cells.…”