Multiple Phenotypic Changes Define Neutrophil Priming

Abstract

Exposure to pro-inflammatory cytokines, chemokines, mitochondrial contents, and bacterial and viral products induces neutrophils to transition from a basal state into a primed one, which is currently defined as an enhanced response to activating stimuli. Although, typically associated with enhanced generation of reactive oxygen species (ROS) by the NADPH oxidase, primed neutrophils show enhanced responsiveness of exocytosis, NET formation, and chemotaxis. Phenotypic changes associated with priming also include activation of a subset of functions, including adhesion, transcription, metabolism, and rate of apoptosis. This review summarizes the breadth of phenotypic changes associated with priming and reviews current knowledge of the molecular mechanisms behind those changes. We conclude that the current definition of priming is too restrictive. Priming represents a combination of enhanced responsiveness and activated functions that regulate both adaptive and innate immune responses.

Filifactor alocismodulates human neutrophil antimicrobial functional responses

“…This result suggests that F. alocis secreted products are not involved in the low ROS levels generated in F. alocis challenged neutrophils. During an inflammatory setting in vivo , quiescent neutrophils can change into a pre-activated phenotype or primed cell due to exposure to inflammatory cytokines such as TNF-α, interleukin (IL)-1β and IL-17 (Kruger, Saffarzadeh, Weber, Rieber, Radsak, von Bernuth, … Hartl, 2015; Miralda, Uriarte, & McLeish, 2017). Primed neutrophils have a more robust response when encountering a second stimulus, but a priming agent, such as TNF-α, by itself does not result in generation of oxidants (Condliffe, Kitchen, & Chilvers, 1998).…”

“…In the present study, we extended these findings to show that 10% serum opsonized F. alocis induced secretory vesicles, gelatinase and specific granule exocytosis, but not azurophil granules; a process that was not dependent on bacterial viability except in the case of the secretory vesicles. Degranulation has been shown to be a critical step in the priming and activation of neutrophils (Miralda, Uriarte, & McLeish, 2017; Uriarte, Rane, Luerman, Barati, Ward, Nauseef, & McLeish, 2011). Previous studies have shown that F. alocis induced the release of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 by epithelial cells which could result in priming and/or activation of human neutrophils (Moffatt, Whitmore, Griffen, Leys, & Lamont, 2011).…”

Therapeutic targeting of neutrophil exocytosis

“…Neutrophils require a first stimulus to prepare them for the release of specific granule contents upon exposure to a second stimulus. This sequential “two‐hit” model for enhanced neutrophil responses is commonly referred to as “priming.” Transmigration in vivo induces extracellular release of 22% of specific granules . Specific granules fuse with nascent phagosomes as part of their general translocation to the plasma membrane .…”

“…Generation of ROS by the NADPH oxidase and release of antimicrobial proteins during granule mobilization provide synergistic antimicrobial activity . Both processes are enhanced, or primed, upon neutrophil exposure to chemokines, cytokines, or microbial and cell products . Recent studies indicate that priming of granule mobilization and oxidase activity are linked.…”

Signaling and functional competency of neutrophils derived from bone-marrow cells expressing the ER-HOXB8 oncoprotein

“…Neutrophils derive from promyeloid progenitors and leave the bone marrow as fully differentiated cells to enter the blood circulation . Unlike other myeloid and lymphoid immune cells, neutrophils do not further differentiate outside the bone marrow but their bactericidal potency can be enhanced by cytokines, chemokines, or microbial products . During infection, the circulating cells are recruited from the blood stream to inflamed tissue following chemotactic gradients, a multistep process that is finely regulated …”