The neutrophil, a polymorphonuclear leukocyte, is the most abundant immune cell in our circulation and is considered classically as the cornerstone of the innate arm of immunity. 1 Approximately 5 × 10 10 -10 11 neutrophils are produced daily in the bone marrow, in order to maintain a steady supply of cells to the circulation and tissues. 2,3 This constant supply is necessary due to the short life span of neutrophils (6-12 hours in mice in the circulation and 5.4 days in humans and within some tissues) and occurs through a well-coordinated developmental process of granulopoiesis, which can adapt quickly and become exaggerated, when needed, to account for increased needs during infection and inflammation.Granulopoiesis or neutrophil development is initiated from hematopoietic stem cells which differentiate into multipotent progenitor (MPP) cells that do not have further potential for self-renewal.MPPs give rise to lymphoid-primed multipotent progenitors (LMPPs) and subsequently to granulocyte-monocyte progenitors (GMPs).GMPs, with the support of the granulocyte colony-stimulating factor (G-CSF), commit to neutrophil differentiation by turning into myeloblasts and subsequently transitioning through the stages of promyelocyte, myelocyte, metamyelocyte, band cell, and finally into mature neutrophils. 4 During the differentiation /maturation process, cells will have evident changes in nuclear morphology, granule content, granular protein expression, proliferative capacity, and transcriptional activity 5,6 and will express distinct cell surface markers. Specifically, primary (azurophil) granules are found at the myeloblast to promyelocyte stage. Secondary (specific) granules are detected at myelocyte and metamyelocyte stages. Tertiary (gelatinase) granules are found at the band cell stage and secretory vesicles are detected only in mature neutrophils. These granules store an arsenal of serine proteases, including elastase, myeloperoxidase, cathelicidins, defensins, and matrix metalloproteinases. 7 During maturation, the neutrophil nucleus will also mature from a round shape into a banded and then a lobulated morphology. With maturation, transcriptional, and proliferative capacity of neutrophils will also diminish, giving rise to what is considered a terminally differentiated cell state. 8

Neutrophil infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease.