Calprotectin-mediated CD69 signaling in periodontitis

7. PROJECT SUMMARY / ABSTRACT Periodontitis is a chronic inflammatory condition characterized by the destruction of the periodontium and is the

leading cause of tooth loss in adults. It is driven by a dysbiotic microbial biofilm that colonizes the gingival sulcus. We seek to identify and characterize the local immune response to the microbial biofilm that leads to periodontitis. Recently, CD69 engagement on T regulatory cells was reported to induce immunosuppressive activities. A

natural ligand for CD69-mediated activation of Tregs is calprotectin (CLP; S100A8 complexed to S100A9; S100A8/A9; MRP8/14). When expressed in stratified squamous epithelia, this divalent cation-binding complex appears to contribute to intraepithelial antimicrobial defense. When released from infected or desquamating

keratinocytes or neutrophils, however, CLP may interact with CD69+ T regulatory or T helper 17 cells, ultimately suppressing the immune response. If so, CLP may function during the initiation of periodontitis contrary to its postulated function as a proinflammatory “alarmin”. Using a global CLP null mouse,

our preliminary data suggest that the net effect of CLP dampens the recruitment of an acute inflammatory infiltrate and limits periodontal bone destruction in a ligature-induced experimental periodontitis model. We will now explore a modified mouse model of ligature-induced periodontitis primed with Porphyromonas gingivalis (Pg).

and in the resolution phase We hypothesize that CLP signals through CD69 during the initiation and resolution phases of experimental periodontal inflammation to dampen the destructive cellular infiltrate in the gingiva. To test our hypothesis, we will: 1: Characterize the differences in the inflammatory cell infiltrate attributable to CLP during the initial

and resolution phases of experimental periodontitis. 2: Determine how Pg-primed Treg cells modulate the recruitment of the initial inflammatory cell infiltrates through CD69 signaling and CLP. 3: Determine the contribution of Pg-primed Th17 cells to modulating recruitment of the initial and resolution phase

and resolution phase inflammatory cell infiltrates attributable to CD69 signaling and CLP. To our knowledge, we are the first group with data suggesting that CLP dampens the innate immune response in a CD69-dependent manner. We have the tools to explain how CLP contributes to recruitment of innate immune

cells by affecting Treg and Th17 cells in vivo using a murine model of periodontitis. Ultimately, we will characterize how CLP and CD69 signaling in Treg and Th17 cells shapes the immune cell environment in the gingiva to drives either protection of periodontal tissues or destruction of alveolar bone. The results obtained

here will be used to design therapeutic interventions directed at boosting or inhibiting the activity of CLP. Critical steps will be identified that might be amenable to targeted therapeutic intervention in humans. Ultimately we aim to reduce the economic and personal burden of periodontal diseases.