Inhibition of Dec1 provides biological insights into periodontal pyroptosis
Shunichi Oka, Xiaoyan Li, Fengzhu Zhang, Nitesh Tewari, Chen Wang, Il-Shin Kim, Liangjun Zhong, Nobushiro Hamada, Yoshiyuki Oi, Makoto Makishima, Yi Liu, Ujjal K. Bhawal
Abstract
Intracellular signaling complexes of the innate immune system orchestrate the development of inflammation. Porphyromonas gingivalis is a commensal bacterium that induces periodontal pyroptosis. The transcription factor Dec1 can regulate the expression of inflammatory molecules. In this study, we investigated whether a deficiency of Dec1 activates/represses Caspase-1 and/or Gasdermin-D in periodontal pyroptosis, resulting in the release of the proinflammatory mediator interleukin-1β. Dec1 expression in human periodontal ligament fibroblasts (HPDLFs) treated with P. gingivalis lipopolysaccharide (LPS) was assessed and pyroptosis activation was determined by microscopy, qRT-PCR and Western blot analysis. Moreover, a siRNA targeting Dec1 was introduced into HPDLFs to determine the function of Dec1 in periodontal pyroptosis and a Dec1-deficient experimental mouse model of periodontitis was used. Treatment of HPDLFs with P. gingivalis LPS-stimulated levels of cleaved-Caspase-1 and cleaved-GSDMD and increased levels of phosphorylated NF-κB and interleukin-1β. In contrast, Dec1 knockdown maintained cellular homeostasis with low levels of pyroptosis. Treatment with P. gingivalis alleviated periodontal pyroptosis in PDLFs of wild-type mice and a Dec1 deficiency subsequently repressed the inflammatory effect of P. gingivalis. These results reveal for the first time the novel function of Dec1 in periodontal pyroptosis, suggesting that Dec1 is a crucial target to prevent periodontal inflammation.