Neutrophil plasticity in inflammation resolution: mechanisms and therapeutic potential

As primary effector cells of the innate immune response, neutrophils exert pivotal regulatory effects on inflammatory responses at the initiation, amplification and resolution stages. This dynamic nature is apparent in multilayered signaling responses, functional plasticity and their mutual actions within the immune network. During early inflammation, neutrophils are rapidly recruited to sites of injury or infection through chemotactic axes, including the interleukin (IL)-8/C-X-C chemokine receptor (CXCR)1/2 axis and the C-X-C motif chemokine ligand 2/CXCR2 axis, as well as by pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). At these sites, they destroy pathogens by phagocytosis, by producing reactive oxygen species (ROS), and through the release of so-called neutrophil extracellular traps (NETs). At the intermediate phase, activation of signaling pathways including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) leads to neutrophil activation and immunity amplification, while NETs support the equilibrium by regulating macrophage, dendritic cell, and T lymphocyte activities. Neutrophil apoptosis and subsequent macrophage-mediated efferocytosis contribute to limiting inflammatory activity and promoting tissue repair during resolution of inflammation; by contrast neutrophil-associated anti-inflammatory and pro-resolving responses, which vary according to the inflammatory context, exhibit a more complex role. Heterogeneous neutrophil populations and functional states in chronic inflammatory lesions and the tumor microenvironment (TME) may show divergent effects on tissue injury and repair. Neutrophils with primarily pro-inflammatory functions can sustain inflammation and tissue destruction, whereas neutrophils displaying anti-inflammatory or reparative programs may contribute to the repair of damaged tissues and the re-establishment of homeostasis. Together, neutrophils perform stage-specific actions across the inflammatory continuum, and their spatiotemporal fine-tuning and signal redirection could become potential targets for precise treatment of infections, autoimmunity, and tumor-related inflammation.