Search

Fibrin gums up the works Plasmin is an abundant plasma protease that cleaves and deactivates the clot-associated protein fibrin. Human deficiencies in plasmin and its inactive proenzyme form, plasminogen (PLG), cause severe inflammation in mucosal tissues such as the mouth and eyes. Silva et al . report that, like humans, mice lacking plasminogen accumulate extravascular fibrin and develop an oral pathology that phenocopies human ligneous periodontitis (see the Perspective by Vicanolo and Hidalgo). The excess fibrin activates neutrophils through the αMβ2 (Mac-1) integrin receptor, which triggers the production of reactive oxygen species and neutrophil extracellular traps. Additionally, certain human polymorphisms in the PLG gene were found to be associated with increased likelihood of developing periodontitis, suggesting that fibrin–neutrophil interactions may be an attractive target for future treatments of this prevalent disease. —STS

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory Th17 cells in human periodontitis. Phenocopying humans, Th17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral Th17 cells, which accumulate in a commensal-independent and IL-6-dependent manner, periodontitis-associated expansion of Th17 cells was dependent upon the local dysbiotic microbiome and required both IL-6 and IL-23. Importantly, Th17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of Th17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in Th17 cell differentiation established human relevance for our murine experimental studies. Indeed, in the oral cavity, human Th17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of Th17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.