Relevance of Caspase-1 and Nlrp3 Inflammasome on Inflammatory Bone Resorption in A Murine Model of Periodontitis

Rocha, Fernanda Regina Godoy; Delitto, Andrea E.; Souza, João Antônio Chaves de; Gonzalez-Maldonado, Laura; Wallet, Shannon M.; Rossa, Carlos

doi:10.1038/s41598-020-64685-y

Cited by 36 publications

(40 citation statements)

References 54 publications

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“…In contrast, A. actinomycetemcomitans infection in THP-1 macrophages can trigger robust expression of AIM2 rather than NLRP3, suggesting that activation of the AIM2 inflammasome may dominantly contribute to the defense against A. actinomycetemcomitans ( 164 ). Similar evidence shows that although NLRP3 expression is increased in RAW 264 cells infected with A. actinomycetemcomitans , it may not be the most vital player in promoting inflammatory bone loss in this scenario: inhibition of ROS and cathepsin B rather than Nlrp3 knockdown can prevent increased IL-1β secretion, and the bone resorption activity of osteoclasts differentiated from Nlrp3 -deficient macrophages of mice with experimental periodontitis induced by A. actinomycetemcomitans is even increased ( 250 , 251 ). However, recent studies have shown that A. actinomycetemcomitans and its cytolethal distending toxin induce caspase-1 cleavage and persistent expression of IL-1β and IL-18 via an NRLP3-dependent pathway in U937 macrophages and THP-1 macrophages by increasing ROS and ATP levels, but not in human gingival epithelial cells ( 252 , 253 ).…”

Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bonmentioning

confidence: 68%

Inflammasomes in Alveolar Bone Loss

2021

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bonmentioning

confidence: 68%

Inflammasomes in Alveolar Bone Loss

2021

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“…A previous study revealed that intracellular LPS or inflammatory caspases were required for the activation of GSDMD ( Rathinam et al, 2019 ). As elevated levels of LPS from gram-negative bacterial and inflammatory caspases were often detected in patients with periodontitis and in murine periodontitis, this provided a prerequisite for the activation of GSDMD and IL-1β release ( Cheng et al, 2017 ; Rocha et al, 2020 ). In this work, we also confirmed that the activation of caspase-4/11 was elevated in human periodontitis samples and in murine periodontitis models and that P. gingivalis (a gram-negative periodontopathogen) induced PDLSC pyroptosis with the cleavage of GSDMD and IL-1β release.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Liu

Wang

et al. 2021

Front. Cell Dev. Biol.

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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.

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“…: (i) NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation; (ii) MCC950 suppresses alveolar bone loss with reduced IL-1β activation and osteoclast differentiation in ligature-induced periodontitis.Several studies have reported the important role of NLRP3 in periodontitis, with the focus on the function of NLRP3 on macrophage12 or periodontal ligament cells 27. To the best of our knowledge, the first report focused on the effects of NLRP3 on osteoclast differentiation in periodontitis, found that NLRP3 inflammasome does not have a relevant role in the inflammatory bone resorption 28. These results are in contrast with those of a study that used a Porphyromonas gingivalis oral colonization model of experimental periodontitis, which showed a significant attenuation of bone resorption in NLRP3-deficient mice 12.…”

mentioning

confidence: 99%