Abstract
Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium that has been strongly associated with localized aggressive periodontitis. The capacity of A. actinomycetemcomitans to produce a leukotoxin (LtxA) that activates pyroptosis in macrophages and induces the release of endogenous danger signals is thought to play a key role in the disease process. The aim of the present study was to investigate the effects of cranberry proanthocyanidins (PACs) on gene expression and cytotoxic activities of LtxA. We showed that cranberry PACs dose-dependently attenuate the expression of genes making up the leukotoxin operon, including ltxB and ltxC, in the two strains of A. actinomycetemcomitans tested. Cranberry PACs (≥62.5 µg/mL) protected macrophages against the cytotoxic effect of purified LtxA. Moreover, cranberry PACs reduced caspase-1 activation in LtxA-treated macrophages and consequently decreased the release of both IL-1β and IL-18, which are known as damage-associated molecular patterns (DAMPs) and contribute to the progression of periodontitis by increasing cell migration and osteoclastogenesis. In addition, cranberry PACs reduced the expression of genes encoding the P2X7 receptor and NALP3 (NACHT, LRR and PYD domains-containing protein 3), which play key roles in pore formation and cell death. Lastly, cranberry PACs blocked the binding of LtxA to macrophages and consequently reduced the LtxA-mediated cytotoxicity. In summary, the present study showed that cranberry PACs reduced LtxA gene expression in A. actinomycetemcomitans and neutralized the cytolytic and pro-inflammatory responses of human macrophages treated with LtxA. Given these properties, cranberry PACs may represent promising molecules for prevention and treatment of the aggressive form of periodontitis caused by A. actinomycetemcomitans.
Highlights
Periodontitis, an inflammatory disease initiated by specific bacteria colonizing subgingival sites, affects the tooth-supporting structures, including the connective tissues and the alveolar bone.Aggregatibacter actinomycetemcomitans has been strongly associated with the initiation and progression of localized aggressive periodontitis (LAP), which affects specific teeth of young individuals [1,2,3]
The present study showed that cranberry PACs reduced LtxA gene expression in A. actinomycetemcomitans and neutralized the cytolytic and pro-inflammatory responses of human macrophages treated with LtxA
LtxA is secreted in the surrounding environment, it has been identified in outer membrane vesicles released by A. actinomycetemcomitans [11]
Summary
Periodontitis, an inflammatory disease initiated by specific bacteria colonizing subgingival sites, affects the tooth-supporting structures, including the connective tissues and the alveolar bone. Aggregatibacter actinomycetemcomitans has been strongly associated with the initiation and progression of localized aggressive periodontitis (LAP), which affects specific teeth (incisors and first molars) of young individuals [1,2,3]. LtxA is secreted in the surrounding environment, it has been identified in outer membrane vesicles released by A. actinomycetemcomitans [11]. These vesicles may contribute to the systemic distribution of the toxin [11] and may modulate the disruption of homeostasis and tissue remodeling processes [12,13]
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