Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Oral Health Research

First Advisor

Zhao Lin

Second Advisor

Sinem E. Sahingur

Abstract

The regulation of inflammatory signaling pathways is critical for proper innate immune responses to pathogens as well as the prevention of chronic inflammation. Ubiquitination, a covalent posttranslational modification, has been identified as a key regulator of multiple signaling cascades, including nuclear factor (NF)-κB. A20 (also known as TNF alpha induced protein 3 or TNFAIP3) has emerged as critical ubiquitin-editing enzyme that functions as an endogenous regulator of inflammation through termination of NF-κB activation as part of a negative feedback loop. Through its function in a plethora of biological processes, aberrant expression and/or function of A20 has been implicated in gastrointestinal, cardiovascular, neurological and pulmonary diseases as well as autoimmune disorders and cancers. However, the role of A20 in the maintenance of periodontal tissue homeostasis is elusive. We now provide evidence that A20 is a critical regulator of periodontal inflammation. Partial loss of A20 promotes an exacerbated inflammatory phenotype associated with increased alveolar bone loss and gingival cytokine production in a murine model of ligature-induced periodontitis. A20 regulates inflammatory responses to keystone oral bacteria, Porphyromonas gingivalis (P. gingivalis), infection and restricts inflammation through its effect on NF-κB signaling and cytokine production in murine and human macrophages. We also provide additional evidence that A20 functions as a modulator of macrophage homeostasis through its regulation of M1 and M2 macrophage polarization states. These discoveries open up new avenues of investigation to evaluate the potential for A20-targeted therapies to alleviate adverse clinical outcomes in periodontitis. Previous data from our lab suggests that A20 protein levels may not be sustained in periodontitis possibly through post-transcriptional regulation. Here, we provide evidence that several different miRNAs known to target A20 in other disease models, are being regulated by pathogenic periodontal bacteria. These results suggest that miRNAs may be a likely mechanism to regulate A20 expression levels post-transcriptionally in the oral cavity as well. Furthermore, we identified Quercetin, an A20-inducing flavonoid, as a natural based therapeutic to attenuate periodontal inflammation and restore an oral microbial dysbiosis. Collectively, these results provide evidence underscoring the critical role of A20 in the maintenance of periodontal tissue homeostasis and pave the way for future translational studies in restoring periodontal health.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-1-2020

Available for download on Tuesday, October 14, 2025

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