Neutrophil extracellular traps and extracellular histones mediate IL-17 inflammation and bone destruction in periodontitis

Abstract Neutrophil infiltration is a hallmark of the inflammatory disease periodontitis, a prevalent oral condition in which Th17 driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that in periodontitis, neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model of periodontitis, we demonstrate that neutrophils infiltrate disease lesions at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanism by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document, in periodontitis patients, significantly elevated levels of NET complexes and of extracellular histones bearing classic NET-associated post-translational modifications. Strikingly, concentrations of NET components in disease lesions and in circulation, significantly correlate with the severity of bone destruction in patients, even in the absence of known confounding systemic disease. Our findings suggest a feed-forward loop in which NETs trigger Th17 immunity to further amplify neutrophil immunopathology in a prevalent human inflammatory disease.