Activation of Notch-1 in oral epithelial cells by P. gingivalis triggers the expression of the antimicrobial protein PLA2-IIA

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P. gingivalis (Pg) is an oral pathogen with the ability to induce oral dysbiosis and periodontal disease. Nevertheless, the mechanisms by which mucosal responses to the oral microbiota in the presence of specific pathogens such as Pg could abrogate the host-microbe symbiotic relationship leading to periodontitis remain unclear. Herein, we identified the Notch-1/PLA2-IIA axis as a new molecular pathway through which Pg could be specifically modulating oral epithelial antimicrobial and inflammatory responses. Pg activated Notch-1, and inhibition or silencing of Notch-1 completely abrogated Pg-induced PLA2-IIA in oral epithelial cells (OECs). Activation of Notch-1 and PLA2-IIA production were associated with Pg-produced gingipains. Other oral Gram-positive and Gram-negative species failed to induce similar responses. Pg enhanced OEC antimicrobial activity through PLA2-IIA. Increased Notch-1 activation correlated with higher PLA2-IIA gingival expression and changes in the abundance of specific oral bacteria phyla during periodontal disease. Oral bacterial species exhibited differential antimicrobial susceptibility to PLA2-IIA. These findings support previous evidence suggesting an important role for epithelial Notch-1 activation and PLA2-IIA production during health and disease at mucosal surfaces, and provide new mechanistic information concerning the regulation of epithelial antimicrobial and pro-inflammatory responses modulated by oral pathogenic bacteria associated with periodontal disease.

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We would like to thank Drs. Richard Lamont (University of Louisville), Ann Progulske-Fox (University of Florida) and Sarah D’Orazio (UK) for their generosity in sharing the TIGK cells, Pg mutant strains for gingipains, and Lm strain respectively. We also thank the Genetics Core from University of Kentucky for their support with Nanostring and 16S sequencing experiments. NIH/NIDCR Grant DE024804 and NIH/NIGMS Grant P20GM103538 supported this research.

Author information


  1. Center for Oral Health Research, College of Dentistry, University of Kentucky, Lexington, KY, USA

    • Ahmad Al-Attar MD, PhD
    • , Yelena Alimova MS
    • , Sreenatha Kirakodu PhD
    • , Anastasia Kozal BS
    • , Michael John Novak BDS, PhD
    •  & Octavio A. Gonzalez DDS, PhD
  2. Department of Statistics, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA

    • Arnold J. Stromberg PhD
  3. School of Dental Medicine, University of Puerto Rico, San Juan, PR, USA

    • Luis Orraca DMD, MS
  4. Caribbean Primate Research Center, University of Puerto Rico, Toa Baja, PR, USA

    • Janis Gonzalez-Martinez PhD
    •  & Melween Martinez PhD
  5. School of Dental Medicine, University of Nevada, Las Vegas, Las Vegas, NV, USA

    • Jeffrey L. Ebersole PhD
  6. Division of Periodontology, College of Dentistry, University of Kentucky, Lexington, KY, USA

    • Octavio A. Gonzalez DDS, PhD


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A.A., Y.A., S.K. designed and performed in vitro experiments, analyzed data, and wrote manuscript; A.K. assisted in vitro experiments; M.J.N., L.O., J.G., M.M., and J.L.E. contributed designing and conducting the nonhuman primate experiments as well as analyzing the data; A.J.S. supported the experimental design and statistical analysis; O.A. design the study, supervised and performed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Octavio A. Gonzalez DDS, PhD.

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