Periodontitis is a chronic inflammatory disease that is the leading cause of periodontal tissue destruction and tooth loss. Treating periodontal disease comes at a high economic cost.. Although triggered by a dysbiosis of the oral microbiota, periodontitis is essentially a disease resulting from a local inflammatory response against a microbial biofilm surrounding the tooth. The impact of infiltrating neutrophils or neutrophil-like cells on destructive T cells is unknown. Our current objective is to determine how these cells regulate destructive T cell responses in a mouse model of chronic periodontitis initiated by Porphyromonas gingivalis (Pg). Activated neutrophils can express the chemokines CCL2 and CCL20 and may amplify the early inflammatory response in periodontitis by helping recruit CCL2- and CCL20-responsive Th17 cells to the inflamed gingiva. Current research has also revealed that neutrophils are not a homogenous group and have different activation states and functions, which may include suppressive capabilities. So-called polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice are phenotypically and morphologically indistinguishable from regular neutrophils. However, this subpopulation of PMNs has the ability to actively suppress T cells. Accordingly, we hypothesize that at initiation of dysbiosis, neutrophils act as positive regulators of Th17 recruitment to the gingiva and subsequently as negative regulators of local T cell clonal expansion during chronic phases of the disease. To test this hypothesis we will pursue two specific aims using novel mice strains generated by us.
Aim 1. Determine the potential of CCL2 and CCL20 produced by neutrophils/PMN-MDSCs to recruit Th17 cells to the oral mucosa during early oral colonization with Pg. We hypothesize that early in Pg- induced dysbiosis, neutrophils aid recruitment of Th17 cells by boosting gingival levels of CCL2 and CCL20. To test our hypothesis we will orally infect experimental mice that carry Ccl2 and/or Ccl20 ablations restricted to neutrophils/PMN-MDSCs with Pg. Mutant mice are expected to recruit fewer Th17 cells to the oral mucosae and lose less alveolar bone than WT mice after Pg-colonization.
Aim 2. Determine the role of arginase-1 produced by neutrophils/PMN-MDSCs in suppressing expansion of oral mucosa T cell populations during persistent oral colonization with Pg. We hypothesize that arginase 1 secreted by PMN-MDSCs or neutrophils suppresses adaptive T cells and innate ?? T cells late during persistent oral Pg exposure. To test our hypothesis we will orally infect experimental mice that carry an arg1 ablation restricted to neutrophils/PMN-MDSCs with Pg. We expect mutant mice to have larger numbers of adaptive T cells and ?? T cells in the oral mucosa and to lose more alveolar bone. Our proposed research is significant because it will examine novel regulatory roles of neutrophils/PMN-MDSCs in periodontitis.
We will determine whether certain white blood cells within the surface of the gum are able to shape the protective characteristics of other immune cells deep in the gum tissues following infection with a gum disease microbe. The results of this research will help us determine which white blood cells in mice, and potentially in humans, either protect or exacerbate gum disease. By identifying these white blood cells, we can develop therapies to manipulate and modulate their behavior to improve gum health.
