Project Details
Description
7. PROJECT SUMMARY / ABSTRACT
Periodontitis is a prevalent chronic inflammatory condition characterized by the destruction of the periodontium
that ultimately leads to tooth loss in adults. It is driven by a dysbiotic microbial biofilm that colonizes the
gingival sulcus around teeth. We seek to identify and characterize the local immune response to the dysbiotic
biofilm that leads to periodontitis. Recently, CD69 engagement on regulatory T cells was reported to induce
immunosuppressive activities. A natural ligand for CD69-mediated activation of regulatory T cells is
calprotectin (S100A8 complexed to S100A9; S100A8/A9). When expressed in stratified squamous epithelia,
this divalent cation-binding heterodimeric complex appears to contribute to intraepithelial antimicrobial defense.
When released from neutrophils or infected or desquamating keratinocytes, however, calprotectin may interact
with CD69+ T regulatory or T helper 17 cells, ultimately suppressing the immune response. If so, calprotectin
may suppressive functions during the initiation of periodontitis contrary to its postulated role as a
proinflammatory “alarmin”. Using a global calprotectin null mouse, our preliminary data suggest that the net
effect of calprotectin 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 novel murine model
of ligature-induced periodontitis primed with Porphyromonas gingivalis (Pg) gavage. We hypothesize that
calprotectin signals through CD69 during the initiation of experimental periodontal inflammation to dampen a
destructive cellular infiltrate into the gingiva. To test our hypothesis, we will: 1: Characterize the differences
in the inflammatory cell infiltrate during the initial stage of experimental periodontitis attributable to
calprotectin. 2. Determine the contribution of CD69 signaling to the recruitment of the initial
inflammatory cell infiltrate in the presence and absence of calprotectin. To our knowledge, we are the
first group with data suggesting that calprotectin dampens the innate immune response. We have the tools to
explain how calprotectin contributes to recruitment of innate immune cells in the gingiva by affecting global
CD69 signaling in vivo using a murine model of periodontitis. We will characterize how calprotectin and CD69
signaling in Treg cells shapes immunosuppression on other effector T cells. Ultimately, we will elucidate
whether calprotectin via CD69 global signaling in the gingiva 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 calprotectin. Critical steps will be identified that might be
amenable to targeted therapeutic intervention in humans aiming at reducing the economic and personal
burden of periodontitis.
Status | Finished |
---|---|
Effective start/end date | 4/1/21 → 3/31/23 |
Funding
- National Institute of Dental and Craniofacial Research: $193,750.00
- National Institute of Dental and Craniofacial Research: $232,125.00
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