Abstract Background Polysulfides are reported to be involved in various important biological processes. N‐acetyl‐l‐cysteine polysulfide with 2 sulfane sulfur atoms (NAC‐S2) regulates diverse toll‐like receptor (TLR) signaling pathways. Here, we aimed to determine the role of NAC‐S2 in periodontitis and explore the potential mechanism. Methods A periodontitis mouse model was established by ligating the subgingival between the first and second molars in wild‐type, TLR4‐/‐, and Myd88‐/‐ mice. Results NAC‐S2 did not affect the proportion of macrophages (CD11b+F4/80+) or neutrophils (CD11b+GR‐1+) in the bone marrow. Mechanically, lipopolysaccharides (LPS), Zymosan A, or poly I: C induced tumor necrosis factor (TNF), interleukin (IL)‐6, and IL‐1β expression in bone marrow‐derived macrophages (BMDMs) could be inhibited by NAC‐S2. On the other hand, NAC‐S2 suppressed the phosphorylation levels of IκB‐α, p65, and IκB kinase (IKK)‐β induced by LPS in BMDMs, while LPS induced phosphorylation of ERK1/2, p38, and transforming growth factor β‐activated kinase 1 (TAK1) could not be affected by NAC‐S2. In wild‐type periodontitis mice, NAC‐S2 administration decreased the cemento‐enamel‐junction–alveolar bone crest (CEJ‐ABC) distance and the relative mRNA expression of TNF, IL‐6, and IL‐1β, while such phenomena could not be observed in TLR4 deficiency or Myd88 deficiency mice. Conclusions All of these results indicate that NAC‐S2 ameliorates TLR4/NF‐κB pathway mediated inflammation in mouse periodontitis model.
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