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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.<\/jats:p>","DOI":"10.1084\/jem.20221751","type":"journal-article","created":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T02:20:58Z","timestamp":1683944458000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":185,"title":["Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-9694","authenticated-orcid":true,"given":"Tae Sung","family":"Kim","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research 1 , , Bethesda, MD, USA"},{"name":"National Institutes of Health 1 , , 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