1. Neutrophil Extracellular Traps (NETs) and NETosis

NETs represent a crucial mechanism by which neutrophils play a vital role in immune defense. NETs are composed primarily of DNA, histones, and granular proteins of neutrophils, which together form a mesh-like structure capable of effectively capturing and killing pathogens. The formation of NETs is closely related to NETosis, a unique form of neutrophil cell death. The formation of NETosis is regulated by multiple factors, including pathogen recognition, release of inflammatory factors, and activation of intracellular signaling pathways. However, under certain pathological conditions, such as autoimmune diseases, NETosis may be overactivated, leading to abnormal formation and accumulation of NETs, which can trigger inflammatory responses and tissue damage.

Note: due to the relation between NETs formation and NETosis, there are studies focusing on “the occurrence of NETosis in neutrophils and NETs formation”. 

2. Reverse Trans-endothelial Migration (rTEM) of Neutrophils

rTEM refers to the process by which neutrophils reverse their conventional migration direction and return from extravascular tissues into the bloodstream after experiencing inflammation or infection. Relative to the classical trans-endothelial migration (TEM), rTEM plays a critical role in regulating inflammation, promoting tissue repair, and aiding in pathogen clearance. Neutrophils remigrate through interactions between surface molecules, such as β2 integrins, and corresponding ligands on vascular endothelial cells, while being finely mediated by various cytokines and chemokines.

3. Tumor-Associated Neutrophils (TANs)

TANs are numerous immune cells in the tumor microenvironment that have complex bidirectional effects of promoting and inhibiting tumor progression. On one hand, TANs can directly exert antitumor effects (N1 phenotype) by releasing cytotoxic granules and reactive oxygen species (ROS) to eliminate tumor cells. On the other hand, TANs may also facilitate tumor progression and metastasis (N2 phenotype) through suppressing T-cell activity and promoting angiogenesis. Within the tumor microenvironment, TANs affect tumor progression by boosting angiogenesis, enhancing tumor invasion and metastasis, suppressing antitumor immune responses, and promoting tumor cell proliferation and survival.

4. Metabolism Reprogramming of Neutrophils

Metabolism Reprogramming of neutrophils is the process by which neutrophils respond to different physiological or pathological conditions and adjust their metabolic pathways.Typically, neutrophils utilize multiple metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and fatty acid oxidation (FAO), to respond to immune challenges, and perform critical functions such as chemotaxis, reactive oxygen species (ROS) production, formation of NETs, and degranulation. Under normal circumstances, glycolysis is their main source of energy. However, in the inflammatory or tumor microenvironment, neutrophils may shift toward other metabolic pathways, such as FAO, to support their effector functions.

5. Neutrophil Senescence

Neutrophil senescence refers to changes in cellular function over time, such as decreased phagocytic activity and bactericidal ability. Although the development and quantity of neutrophils do not seem to undergo systematic changes with age, their function declines in older adults. Additionally, age-related alterations in the tissue environment can reprogram neutrophils. Notably, neutrophil senescence is also regulated by the microbiota.