Background and Objectives Periodontal pathogens initiate various diseases and induce inflammatory host responses. The activation of inflammasomes triggers caspase‐1 and interleukin (IL)‐1β‐mediated pyroptosis via gasdermin D (GSDMD). Differentiated embryo chondrocyte 2 (Dec2) is a transcription repressor that controls the expression of genes involved in innate immune and inflammatory responses. However, the effects of Dec2 on inflammasome‐induced pyroptosis in periodontal tissues remain elusive. This study aimed to characterize the activation of Dec2 inflammasomes that contribute to P. gingivalis lipopolysaccharide (LPS)‐induced pyroptosis and its functional and regulatory importance in periodontal inflammation. Materials and Methods Human gingival fibroblasts (HGFs) and human periodontal ligament fibroblasts (HPDLFs) were stimulated with P. gingivalis LPS in vitro. An experimental periodontitis mouse model (wild‐type (WT) and Dec2KO) was established to profile periodontal pyroptosis. Results The results demonstrate that P. gingivalis LPS activates caspase‐1, caspase‐11, and NF‐κB in HGFs and in HPDLFs. siRNA knockdown of Dec2 stimulated the induction and further upregulated LPS‐induced pyroptosis in HGFs and HPDLFs, resulting in the release of IL‐1β. Further, a deficiency of Dec2 alleviated periodontal pyroptosis via the transcriptional induction of GSDMD. In addition, P. gingivalis‐induced IL‐1β expression and Dec2‐deficient mice subsequently increased the inflammatory effect of P. gingivalis in HGFs and in HPDLFs, confirming the importance of Dec2 in the activation of inflammasomes and the regulation of pyroptosis. Conclusion Our results demonstrate that Dec2 alleviates periodontal pyroptosis by regulating the expression of NF‐κB, caspase‐1 and GSDMD, suggesting that Dec2 is a crucial component of inflammasome activation and subsequent pyroptosis.
Purpose Macrophages play crucial roles as early responders to bacterial pathogens and promote/ or impede chronic inflammation in various tissues. Periodontal macrophage-induced pyroptosis results in physiological and pathological inflammatory responses. The transcription factor Dec2 is involved in regulating immune function and inflammatory processes. To characterize the potential unknown role of Dec2 in the innate immune system, we sought to elucidate the mechanism that may alleviate macrophage pyroptosis in periodontal inflammation. Methods Porphyromonas gingivalis lipopolysaccharide (LPS) was used to induce pyroptosis in RAW 264.7 macrophages. Subsequently, we established an LPS-stimulated Dec2 overexpression cellular model in macrophages. Human chronic periodontitis tissues were employed to evaluate potential changes in inflammatory marker expression and pyroptosis. Finally, the effects of Dec2 deficiency on inflammation and pyroptosis were characterized in a P. gingivalis -treated experimental periodontitis Dec2 -knockout mouse model. Results Macrophages treated with LPS revealed significantly increased messenger RNA expression levels of Dec2 and interleukin (IL)-1β. Dec2 overexpression reduced IL-1β expression in macrophages treated with LPS. Overexpression of Dec2 also repressed the cleavage of gasdermin D (GSDMD), and the expression of caspase-11 was concurrently reduced in macrophages treated with LPS. Human chronic periodontitis tissues showed significantly higher gingival inflammation and pyroptosis-related protein expression than non-periodontitis tissues. In vivo , P. gingivalis- challenged mice exhibited a significant augmentation of F4/80, tumor necrosis factor-α, and IL-1β. Dec2 deficiency markedly induced GSDMD expression in the periodontal ligament of P. gingivalis -challenged mice. Conclusions Our findings indicate that Dec2 deficiency exacerbated P. gingivalis LPS-induced periodontal inflammation and GSDMD-mediated pyroptosis. Collectively, our results present novel insights into the molecular functions of macrophage pyroptosis and document an unforeseen role of Dec2 in pyroptosis.
Pro-infl ammatory cytokines activate the fi broblasts that reside in periodontal tissues and the polymorphonuclear leukocytes (PMNs) that are responsible for a substantial part of the destruction caused by the host response. The resident anaerobic bacteria interact with host inflammatory reactions leading to a hypoxic environment in the periodontal pocket. Expression of the transcription factor Differentiated Embryonic-Chondrocytes Expressed Gene 1 (DEC1) is regulated by hypoxia, growth factors and cytokines. To reveal the biological relevance of hypoxia in periodontal infl ammation, we examined the role of DEC1 in the responses of human periodontal ligament cells to treatment with lipopolysaccharide (LPS), P. gingivalis and/or hypoxia. We found significantly increased levels of DEC1 after hypoxic or inflammatory stimulation of periodontal ligament cells. To further characterize the role of DEC1 in that process, inhibition by DEC1 siRNA was used in the experiments. The results demonstrated that treatment with the DEC1 siRNA inhibited the effects of LPS and hypoxia. Immunohistochemistry performed on an experimental animal model of periodontitis revealed an increase of PMN immunoreactivity, which validated the importance of the in vitro results. Treatment of DEC1-knockout mice with P. gingivalis decreased the production of PMN in periodontal ligament cells. These results demonstrate that DEC1 interference in the pathophysiological process of hypoxia has fundamental relevance for periodontal defenses.
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