Model of NET histone–driven inflammation in periodontitis. Pathogenic bacteria are likely the triggers of NETosis. NET formation leads to the release of NET-associated histones that promote Th17 differentiation directly via TLR2 signaling. In addition, histones induce cytokines in macrophages that promote Th17 proliferation and survival. Th17 cells instruct the epithelium to upregulate neutrophil chemokines that recruit more neutrophils and amplify inflammation via a possible feedback loop. Persistent periodontitis inflammation may also exert its impact systemically on the vasculature by releasing NET histones or downstream cytokines into the circulation or by sustaining pathogenic Th17 cells that disseminate and act systemically.