Periodontal Inflammation-Triggered by Periodontal Ligament Stem Cell Pyroptosis Exacerbates Periodontitis.

Qin Chen,Guanlin Qu,Duohong Zou,Jianfeng Lan,Lu Chen,Chi Yang,Dingyu Wang,Xingguang Liu,Qianyang Xie,Jing Li,Xiaohan Liu,Sujuan Niu,Jisi Zheng

doi:10.3389/fcell.2021.663037

Abstract

Periodontitis is an immune inflammatory disease that leads to progressive destruction of bone and connective tissue, accompanied by the dysfunction and even loss of periodontal ligament stem cells (PDLSCs). Pyroptosis mediated by gasdermin-D (GSDMD) participates in the pathogenesis of inflammatory diseases. However, whether pyroptosis mediates PDLSC loss, and inflammation triggered by pyroptosis is involved in the pathological progression of periodontitis remain unclear. Here, we found that PDLSCs suffered GSDMD-dependent pyroptosis to release interleukin-1β (IL-1β) during human periodontitis. Importantly, the increased IL-1β level in gingival crevicular fluid was significantly correlated with periodontitis severity. The caspase-4/GSDMD-mediated pyroptosis caused by periodontal bacteria and cytoplasmic lipopolysaccharide (LPS) dominantly contributed to PDLSC loss. By releasing IL-1β into the tissue microenvironment, pyroptotic PDLSCs inhibited osteoblastogenesis and promoted osteoclastogenesis, which exacerbated the pathological damage of periodontitis. Pharmacological inhibition of caspase-4 or IL-1β antibody blockade in a rat periodontitis model lead to the significantly reduced loss of alveolar bone and periodontal ligament damage. Furthermore, Gsdmd deficiency alleviated periodontal inflammation and bone loss in mouse experimental periodontitis. These findings indicate that GSDMD-driven PDLSC pyroptosis and loss plays a pivotal role in the pathogenesis of periodontitis by increasing IL-1β release, enhancing inflammation, and promoting osteoclastogenesis.

Highlights

Periodontitis is one of the most prevalent infectious human inflammatory diseases and is distinguished by the progressive destruction of the tooth-supporting tissues and by the inflammatory reaction associated with gram-negative anaerobic bacteria in dental biofilms (Pihlstrom et al, 2005; Hajishengallis, 2015)
X-ray imaging combined with clinical examination demonstrated that periodontitis patients showed obvious alveolar bone resorption, gingival recession, and reduced periodontal tissue adhesion compared with healthy patients (Figure 1A)
Caspase-4 was highly expressed in the periodontal tissues of periodontitis patients. These findings suggested that caspase-4 was activated in periodontitis tissues, leading to GSDMD cleavage and IL-1β release

Summary

Introduction

Periodontitis is one of the most prevalent infectious human inflammatory diseases and is distinguished by the progressive destruction of the tooth-supporting tissues and by the inflammatory reaction associated with gram-negative anaerobic bacteria (such as Porphyromonas gingivalis and Treponema denticola) in dental biofilms (Pihlstrom et al, 2005; Hajishengallis, 2015). Under this sustained inflammatory condition, the periodontal tissues (including alveolar bone, periodontal ligament, and root cementum) are destroyed, and the regeneration function of these attachment apparatuses is damaged, eventually leading to tooth loss and chewing dysfunction (Kinane et al, 2017). The molecular mechanism of PDLSC dysfunction and loss in periodontitis remains unclear, and whether abnormal PDLSCs are involved in the pathogenesis of periodontitis is unknown

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Results

Conclusion