Fraser, D.; Theofilou, V. I.; Greenwell-Wild, T.; Brenchley, L.; Kanasi, E.; Wang, C.; Moutsopoulos, N.

The oral mucosa is a prototypical human barrier reliant on neutrophils for homeostasis, as both neutrophil deficiency and excessive activation are linked to immunopathology. Yet, whether neutrophils acquire tissue-specific states in health or disease remains unclear. We incorporated single-cell RNA sequencing, spectral flow cytometry, and spatial proteomics across tooth-associated oral mucosa (gingiva) and interconnected compartments of blood and oral cavity to define neutrophil tissue specification in healthy individuals and patients with periodontitis, a neutrophil-dominated inflammatory disease. In health, mucosal neutrophils adopt discrete immunoregulatory states despite constant microbial exposure and mechanical injury. Periodontitis disrupts these programs through infiltration of blood-like neutrophil subsets, increased transcriptional noise, and heightened effector activation. Strikingly, oral inflammation systemically imprints on circulating neutrophils, marked by the expansion of a Rho-GTPase regulatory program that is shared across diverse human inflammatory conditions. Together, these findings establish a framework for understanding how localized tissue inflammation affects both neutrophil plasticity at barrier surfaces and conditioning of systemic neutrophil states with broad implications for inflammatory disease pathogenesis.