Journal of Innate Immunity · Published 2026-07-02 · DOI 10.1159/000553300
Shikha Srivastava, Aruna Vashista, Abidemi Ruth Idowu, Madhavi J. Rane, Kenneth R. McLeish, Richard J. Lamont, Silvia M. Uriarte
Introduction: Dysregulated neutrophil functions play a crucial role in the onset and progression of periodontitis. Peptoanaerobacter stomatis is an emerging oral bacterium associated with periodontitis and is known to activate neutrophils through TLR2/6, leading to ROS production, granule release, and NET formation. In this study, we characterized MAPK kinases that regulate these neutrophil responses and determined the mechanism responsible for bacterial killing. Methods: Human neutrophils were challenged with P. stomatis, and kinase activation was assessed by immunoblot. Functional relevance was tested using selective kinase inhibitors prior to bacterial exposure. Neutrophil responses measured included ROS production by kinetic fluorometric assay, degranulation by flow cytometry, and NET formation using immunofluorescence and immunoblotting. Bacterial killing was determined by a CFU assay. Results: P. stomatis activated ERK, p38, PI3K/AKT MAPKs and, Src, and Syk tyrosine kinases in neutrophils. Inhibition of all kinases except AKT significantly reduced ROS production. Because TAK1 is an upstream regulator of MAPK signaling, its role was also evaluated. Degranulation was mainly regulated by TAK1 and p38, with partial involvement of ERK and Src. NET formation required TAK1, ROS, and PAD4. TAK1 and degranulation inhibition markedly decreased bacterial killing, whereas inhibition of ROS or NET had no effect. Conclusion: These findings demonstrate that although P. stomatis evades ROS- and NET-mediated killing, it remains susceptible to TAK1-mediated neutrophil degranulation, identifying degranulation as the primary mechanism for bacterial clearance.
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Srivastava, S., Vashista, A., Idowu, A., et al. (2026). Neutrophil killing of Peptoanaerobacter stomatis requires TAK1-driven degranulation.. Journal of Innate Immunity. https://doi.org/10.1159/000553300