# SGK1 and the control of periodontal inflammation

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $420,339

## Abstract

Abstract
Macrophage polarization enables macrophages adapt to various microenvironmental cues and adopt a spectrum
of functional phenotypes. These are generally classified into classically activated (pro-inflammatory, M1) and
alternatively activated (pro-healing, M2) categories. The M1/M2 balance determines the extent and severity of
inflammatory responses and tissue damage. However, the signaling pathway(s) and cues driving
macrophage polarization in the oral cavity's infectious milieu are largely unknown. Yes-associated protein
(YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators implicated
in inflammation regulation and macrophage polarization in a context-dependent manner. Despite the
observation of aberrant YAP1/TAZ expression in gingival tissues from patients with periodontitis, the triggers
and mechanisms of YAP1/TAZ signaling in regulating macrophage polarization in periodontium remain
unclear. Our previous R01 study unveiled the suppressive role of serum- and glucocorticoid- inducible kinase
(SGK) 1 in the immune response to the oral pathogen. Using Porphyromonas gingivalis (Pg) as a model
organism, in this renewal project, we aim to investigate the regulation of YAP1 by SGK1 in Pg-stimulated
macrophages and its subsequent impact on macrophage polarization, thereby revealing a novel
regulatory module, SGK1-YAP1, in periodontal inflammation. Preliminary results showed that (i) SGK1
inhibition remarkably decreases YAP1 phosphorylation and increases its nuclear retention in Pg-stimulated
macrophages; (ii) Pg infection enhances YAP1 phosphorylation and promotes its retention in the cytoplasm, and
the ubiquitin-proteasome inhibitor further augments YAP1 expression; (iii) YAP1 inhibition suppresses
macrophage polarization towards M1 phenotypes; and (iv) sgk1 deficiency increases nuclear YAP1 expression
and the M1/M2 ratio in the gingival tissue from mice subjected to repeated Pg infection. These findings lead to
our hypothesis that YAP1 cytoplasmic retention and expression are controlled by SGK1 in response to
Pg challenge. This control mechanism limits macrophage polarization towards M1 phenotypes, thereby
preventing tissue damage and periodontal inflammation. To test this hypothesis, we will (i) determine and
characterize the regulation of YAP1 by SGK1 in innate immune cells in response to Pg; (ii) functionally dissect
SGK1-YAP1 signaling pathways in macrophage polarization upon Pg challenge; (iii) assess the effect of SGK1-
YAP1 signaling in vivo on macrophage polarization and disease process induced by Pg using murine infection
models. Successful completion of this study will identify SGK1 as a novel regulator of YAP1/TAZ signaling,
functioning through dual mechanisms of phosphorylation and ubiquitination. For the first time, we will delineate
the alternative macrophage polarization mediated by Pg via SGK1-YAP1 signaling. This work not only advances
our understanding of macrophage polarizati...

## Key facts

- **NIH application ID:** 10980572
- **Project number:** 2R01DE026727-06
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Huizhi Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,339
- **Award type:** 2
- **Project period:** 2017-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980572

## Citation

> US National Institutes of Health, RePORTER application 10980572, SGK1 and the control of periodontal inflammation (2R01DE026727-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10980572. Licensed CC0.

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