Abstract
In periodontal health, oral streptococci constitute up to 80% of the plaque biofilm. Yet, destructive inflammatory events of the periodontium are rare. This observation suggests that oral streptococci may possess mechanisms to co-exist with the host. However, the mechanisms employed by oral streptococci to modulate the innate immune response have not been well studied. One of the key virulence factors produced by oral streptococci is hydrogen peroxide (H2O2). In mammalian cells, H2O2 triggers the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key pathway mediating antioxidant defence. This study aimed to determine (1) if H2O2 producing oral streptococci activated the Nrf2 pathway in macrophages, and (2) if the activation of Nrf2 influenced the innate immune response. We found that oral streptococci downregulated the innate immune response in a H2O2 dependent manner through the activation of the Nrf2. The activation of the Nrf2 signalling pathway led to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFĸB), the key transcription factor regulating pro-inflammatory response. This study showed for the first time that oral streptococci are unlikely passive bystanders but could play an active role in the maintenance of periodontal health by preventing overt inflammation.
Highlights
In periodontal health, oral streptococci constitute up to 80% of the plaque biofilm
To determine if H 2O2 producing oral streptococci modulated the Nrf[2] signalling pathway, Raw 264.7 cells stably expressing the antioxidant response element (ARE)-SEAP reporter were infected with H2O2 producing (S. mitis and S. oralis), and H2O2 non-producing oral streptococci species (S. mutans) (Fig. 1a)
The expression of the antioxidant genes namely, heme oxygenase-1 (HO-1) (Fig. 1c) and glutathione Peroxidase-3 (GPx-3) (Supplementary Fig. 1a) corroborated with the findings of the nuclear factor erythroid 2-related factor 2 (Nrf2)-ARE reporter assay where S. mitis and S. oralis significantly activated the expression of these genes but not S. mutans
Summary
Oral streptococci constitute up to 80% of the plaque biofilm. The mechanisms employed by oral streptococci to modulate the innate immune response have not been well studied. This study aimed to determine (1) if H2O2 producing oral streptococci activated the Nrf[2] pathway in macrophages, and (2) if the activation of Nrf[2] influenced the innate immune response. The gingiva is exposed to large amounts of oral streptococci, destructive inflammation is rare, suggesting that these bacterial species likely possess mechanisms that modulate the innate immune response, facilitating co-existence with the host. It has been put forth that H 2O2 production likely contributes to shaping the biofilm composition towards a microbiome compatible with health It is currently unknown if H 2O2 secreted by oral streptococci modulates the innate immune response
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