Tissue-resident cells including macrophages, dendritic cells, and endothelium detect these signals, initiating neutrophil recruitment. Tissue injury leads to the release of an array of signals, including damage-associated molecular patterns (DAMPs) from damaged cells or pathogen-associated molecular patterns (PAMPs) in infection. Since the mechanisms by which neutrophils are integrated in resolution are likely context-dependent, we also highlight neutrophil contributions to repair in different organs. In this Review, we outline the neutrophil’s role in tissue injury and repair, focusing on its emerging role in resolving inflammation and participation in repair. Yet, despite encouraging advancements in many areas in recent years, some fundamentally unresolved questions remain ( 20). Tumors may also hijack these properties to aid in growth and metastasis ( 19). It is now apparent that neutrophils have crucial homeostatic functions in various organ systems ( 14, 15): they interact with cells of the innate and adaptive immune system to direct immune responses ( 16), are implicated in chronic inflammatory diseases ( 17), experience shaping by the microbiome ( 18), and contribute to injury repair. Furthermore, the identification of Ly6G as a lineage-specific neutrophil membrane protein that can be used to track or deplete neutrophils and the generation of the “Catchup mouse,” a Ly6G neutrophil-specific, Cre-based reporter system driven by the Ly6G promoter combined with fluorescent tdTomato expression, have substantially advanced the study of neutrophils in vivo ( 13). Advanced techniques, such as intravital microscopy, genetic fate mapping, and single-cell sequencing, have driven considerable research in the field, spawning studies into more complex neutrophil biology. The prevailing and rather simplistic view of the neutrophil has undergone substantial revision in the past decade, and numerous novel paradigms have emerged ( 12). While effective in capturing bacteria, NETs produced in infections and noninfectious perturbations have been postulated to cause bystander tissue damage ( 11). Adding to this was the discovery of NETosis ( 10), a novel killing mechanism by which neutrophils release neutrophil extracellular traps (NETs), nuclear DNA coated with histones, proteases, and granular and cytosolic proteins to entrap bacteria. Overexuberant neutrophil recruitment was associated with collateral tissue damage, defective healing, and chronic inflammation ( 2). Upon completion of their tasks, neutrophils were thought to commit suicide on the battlefield. However, until recently, the prevailing view of neutrophils was that of simple foot soldiers of the innate immune system: equipped with a lethal arsenal of proteases and oxidants, neutrophils rapidly invade sites of infection to eradicate pathogens and prevent their spread ( 8, 9). Neutrophil function was subsequently studied by Élie Metchnikoff, widely considered the father of cellular innate immunity, who first described recruitment of phagocytic cells to an injury in starfish embryos ( 6, 7). The works of Paul Ehrlich in the late nineteenth century first recognized heterogeneity of leukocytes and identified one unique cell with a polymorphous nucleus as the “neutrophil” ( 1, 5). Neutrophils act as the first responders of the innate immune system, and their crucial role in fighting invading pathogens is well established and best exemplified by the severe susceptibility of neutropenic patients to infections ( 3, 4). Neutrophils are the most abundant immune cells, constituting about 60% to 70% of all leukocytes in human blood ( 1, 2). This Review scrutinizes the role of neutrophils in tissue damage and repair, discussing recent findings and raising unresolved questions around this intriguing immune cell. Novel concepts include the idea that neutrophils are key to revascularization and subsequently reverse-transmigrate back to the vasculature, actively leaving sites of tissue damage to re-home to functional niches in the lung and bone marrow. Now, the view of neutrophils as indiscriminate killers seems to be changing as evolving evidence suggests that neutrophils actively orchestrate resolution of inflammation and contribute to tissue repair. However, the presence of neutrophil infiltration into sterile injuries (in the absence of infections) suggests additional roles for these cells. Traditionally, neutrophils were thought to cause collateral tissue damage before dying at the site. Equipped with a plethora of antimicrobial molecules, neutrophils invade sites of inflammation to eradicate pathogens and clear debris. Neutrophils are the most abundant immune cells in humans and serve as first responders to a myriad of host perturbations.
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