Disruption of Monocyte and Macrophage Homeostasis in Periodontitis

Objectives: Monocytes and macrophages are major cellular components of the innate immunity that play essential roles in tissue homeostasis. The contribution of different subsets of monocytes/macrophages to periodontal health and disease has not been fully elucidated. We hypothesized that the monocyte/macrophage signaling is perturbed in periodontitis-affected sites versus periodontally-healthy sites.
Methods: Pairs of gingival tissue samples (each from a periodontally healthy and a periodontitis-affected site of the same patient) were harvested from 21 patients undergoing periodontal surgery. Each sample was processed to form a single-cell suspension, and a flow cytometry panel was designed and validated to study monocyte/macrophage phenotypes. In separate experiments, the transcriptional changes associated with a pro-inflammatory phenotype were also examined in monocyte/macrophage subsets obtained from peripheral blood of patients with type 2 diabetes mellitus (T2DM) versus diabetes-free controls.
Results: A significantly higher proportion of intermediate and non-classical monocytes was observed in periodontitis-affected tissues compared to healthy tissues. These monocytes overexpressed HLA-DR and PDL1 molecules, suggesting their activated inflammatory status. PDL1 increase was specific to intermediate monocytes. The ratio of M1(pro-inflammatory)/M2(resolution) macrophages was also significantly higher in periodontally-affected sites. We found a significantly higher expression of PDL1 in monocytes and M1 macrophages in periodontitis-affected sites compared to controls. Importantly, we identified a subpopulation of M1 macrophages present in periodontally-affected tissues which expressed high levels of CD47, a glycoprotein of the immunoglobulin family that plays a critical role in self-recognition and impairment of phagocytosis. Analysis of the transcriptional landscape of circulating monocytes and macrophages in T2DM revealed a significant elevation of pro-inflammatory transcription factors STAT1 and IRF1, and repression of anti-inflammatory JMJD3.
Conclusions: Our data provide novel insights into the disruption of myeloid-derived cell homeostasis in periodontitis and highlight a potentially significant role of these cell types in its pathogenesis.