Treponema denticola dentilisin triggered TLR2/MyD88 activation upregulates a tissue destructive program involving MMPs via Sp1 in human oral cells.

Autor: Ganther S; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Radaic A; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Malone E; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Kamarajan P; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Chang NN; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Tafolla C; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Zhan L; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America., Fenno JC; Department of Biological and Material Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan, United States of America., Kapila YL; Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2021 Jul 13; Vol. 17 (7), pp. e1009311. Date of Electronic Publication: 2021 Jul 13 (Print Publication: 2021).
DOI: 10.1371/journal.ppat.1009311
Abstrakt: Periodontal disease is driven by dysbiosis in the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola, is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed significant upregulation of genes associated with extracellular matrix organization and degradation including potentially tissue-specific inducible MMPs that may play novel roles in modulating host immune responses that have yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula, failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of expression of either abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs while a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola-mediated activation of TLR2/MyD88 lead to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola-dependent MMP expression. Taken together, these data suggest that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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