Friday, May 9, 2025
5/9/2025
Redox Regulation of Gingival Inflammation - Project Summary Abstract PI: Bagaitkar Periodontal diseases are highly common infectious diseases. Chronic inflammation in periodontitis results in the progressive destruction of hard and soft tissues and enhances susceptibility to other systemic disease. The host factors that regulate the magnitude, nature and persistence of inflammatory responses in the oral are incompletely understood. We have previously shown that reactive oxygen species (ROS) generated by the activation of leukocyte NADPH oxidase enzyme complex plays a critical role in dampening hyperinflammatory responses. Oxidase deficiency in mice resulted in profound inflammation characterized by dysregulated neutrophil and macrophages responses and resolution delays. These data support a somewhat counterintuitive role for ROS in limiting host inflammation. Whether oxidants modulate inflammatory pathways in the oral cavity is unclear. Our central hypothesis is that the NADPH oxidase derived-ROS, independent of their antimicrobial functions, play key roles in redox modulation of neutrophil and macrophage effector functions in vitro and in vivo. Further, we hypothesize that while excessive amounts of ROS are associated with the pathophysiology of periodontal diseases, low-level, localized ROS responses are immuno-regulatory. These hypotheses will be tested in two specific aims. 1) Determine the role of NADPH oxidase in the regulation of PMN effector functions in acute responses in the gingiva. 2) Determine the role of NADPH oxidase in the modulation of macrophage function and resolution of gingival inflammation. The use of conditional knockout mice that lack NADPH oxidase activity selectively in neutrophils or macrophages will enable us to specifically determine the role of oxidants in a cell intrinsic manner in vivo. The data generated by these studies will shed key mechanistic insights in our understanding of immune pathways relevant in gingival inflammation and their regulation by oxidants. Further, our studies are also highly relevant in understanding the immunopathology of chronic granulomatous disease, a life-threatening immunodeficiency caused by inherited mutations in NADPH oxidase subunit genes.
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