Nisin bacteriocin blocks T. denticola-triggered MMP2 activation and pathogen internalization via TLR2

We examined Treponema denticola-induced dysregulation of toll-like receptor (TLR) signaling and its downstream effects on matrix metalloproteinase 2 (MMP2) expression and activation in periodontal cells, and whether the antimicrobial peptide nisin could modulate this process. T. denticola and its outer membrane protease dentilisin/PrtP activated MMP2, whereas a dentilisin/PrtP-deficient T. denticola mutant did not, and nisin attenuated this response. Dentilisin/PrtP directly activated recombinant MMP2 in vitro. T. denticola-mediated MMP2 activation was TLR2-dependent, since TLR2 suppression abrogated MMP2 activation, reduced MMP2 mRNA expression, and reduced T. denticola internalization. Nisin significantly inhibited T. denticola internalization. Computational modeling suggests dentilisin/PrtP directly binds pro-MMP2, whereas nisin binds dentilisin/PrtP but not pro-MMP2. Thus, nisin may interfere with MMP2 activation by binding to dentilisin/PrtP. These findings reveal a novel mechanism by which T. denticola and nisin regulate MMP2, and underscore nisin’s potential as a therapeutic for modulating bacterial-mediated tissue damage during periodontal disease.