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

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.

Cannabinoid control of gingival immune activation in chronically SIV-infected rhesus macaques involves modulation of the indoleamine-2,3-dioxygenase-1 pathway and salivary microbiome

“…Notable differentially upregulated genes with critical roles in the pathogenesis of HIV infection and periodontal disease ( Figure 1 a ) included IDO1 (a marker of immune activation), 24 25 IL21R (proliferation of T, B, and NK cells), 26 CXCL10 (neutrophil migration and periodontal bone loss) 27 , 28 , 29 , MMP12 (gingival extracellular matrix degradation), 30 31 IRF1 & IRF7 (innate and adaptive immune response) 32 , VCAM1 (leukocyte-endothelial adhesion/migration), 33 LYN (inflammatory response to bacterial LPS), 33 TLR2 (immune response to bacterial lipoproteins and lipopeptides), 34 TRIM5 and SAMHD1 (HIV/SIV restriction), ALOX5AP (Leukotriene synthesis), GZMA and GZMH (chronic inflammation and antiviral response), KLK6 (inflammation), CD163 (anti-inflammatory macrophages) and GSDMD (bactericidal activity). 35 36

Figure 1 Long-term low dose THC administration inhibits proinflammatory gene expression in gingiva of chronically SIV-infected RMs. Volcano plot shows the relationship between fold-change (X-axis) and statistical significance (Y-axis) of differentially expressed mRNAs in VEH/SIV ( a ) and THC/SIV ( d ) RMs relative to controls and in VEH/SIV relative to THC/SIV RMs ( g ).

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PANoptosis: A New Insight Into Oral Infectious Diseases

“…Experiments in a mouse model of experimental periodontitis confirmed that GSDMD deficiency alleviates periodontal inflammation and bone loss ( 13 ). Moreover, CDK9 inhibition decreases necroptosis and reduces inflammatory bone resorption in mice with bacteria-induced periodontitis ( 99 ).…”

“…Notably, elevated levels of RIPK1, phosphorylated RIPK3, MLKL, phosphorylated MLKL, and FLIPL are common in gingival epithelia and connective tissues from CP patients, indicating the presence of necroptosis during progression of periodontitis ( 10 ). Importantly, increased expression of IL-1β in gingival crevicular fluid correlates significantly with the severity of periodontitis ( 13 ). Thus, PANoptosis is thought to be one of the pathogenic mechanisms underlying persistent inflammation observed in periodontal disease.…”

Pyroptosis-Mediated Periodontal Disease

“…In clinical practice, clinicians frequently face situations where the periodontal or peri-implant tissues overreact to a stimulus promoted by dental materials or even do not respond to therapies, leading to inflammation. In these situations, the claim is that the body is not accepting the treatment, rehabilitation, or therapy [ 1 , 2 , 3 , 4 ]. Indeed, it is very likely that processes are occurring inside the cells to cause such exacerbated inflammation.…”

“…Thus, the mechanisms of pyroptosis involve different major signalling pathways, all activating the downstream of GSDMD. Finally, cytoplasmic molecules, such as interleukins-1β (IL-1β) and -18 (IL-18), are released from the pores formed by GSDMD and trigger a robust inflammatory response ( Figure 1 ) [ 2 , 9 , 10 ]. Thus, the occurrence of pyroptosis can be determined by a combination of markers, including the activation of caspases-1, -4, -5, and -11, the cleavage of GSDMD, and the maturation and release of IL-1β and IL-18 [ 9 ].…”