# Calprotectin-mediated CD69 signaling in periodontitis

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $449,542

## Abstract

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 a...

## Key facts

- **NIH application ID:** 10298399
- **Project number:** 1R01DE030095-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** MASSIMO COSTALONGA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,542
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298399

## Citation

> US National Institutes of Health, RePORTER application 10298399, Calprotectin-mediated CD69 signaling in periodontitis (1R01DE030095-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10298399. Licensed CC0.

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