Targeting the Nod-like receptor protein 3 Inflammasome with inhibitor MCC950 rescues lipopolysaccharide-induced inhibition of osteogenesis in Human periodontal ligament cells

Peng, Wei; Zhang, Bo; Sun, Zhengfan; Zhang, Meifeng; Guo, Ling

doi:10.1016/j.archoralbio.2021.105269

Cited by 6 publications

(3 citation statements)

References 40 publications

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“…Our data showing that EMD significantly reduced the expression of IL-18 in primary macrophages and that NLRP3 and CAS1 specific inhibitors (MCC950 and Ac-YVADcmk, respectively) exert a similar activity, can be considered indirect support for EMD to attenuate pyroptosis activity. These findings are in line with other observations showing that MCC950 inhibited IL-18 release in THP1 and monocytes [36,37], reversed the forced IL-1β and IL-18 expression on periodontal ligament fibroblasts [38], HCT116 colorectal cells [39], and canine kidney epithelial cells [40]. Furthermore, Ac-YVAD-cmk reduced the forced expression of IL-18 in whole blood cells [41], in THP-1 cells [42], and also in sepsis-induced acute kidney injury [43].…”

Section: Discussionsupporting

confidence: 93%

Enamel Matrix Derivative Decreases Pyroptosis-Related Genes in Macrophages

Sordi

Cruz

Panahipour

et al. 2022

IJMS

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Background: Pyroptosis is a caspase-dependent catabolic process relevant to periodontal disorders for which inflammation is central to the pathophysiology of the disease. Although enamel matrix derivative (EMD) has been applied to support periodontal regeneration, its capacity to modulate the expression of pyroptosis-related genes remains unknown. Considering EMD has anti-inflammatory properties and pyroptosis is linked to the activation of the inflammasome in chronic periodontitis, the question arises whether EMD could reduce pyroptosis signalling. Methods: To answer this question, primary macrophages obtained from murine bone marrow and RAW 264.7 macrophages were primed with EMD before being challenged by lipopolysaccharide (LPS). Cells were then analysed for pyroptosis-signalling components by gene expression analyses, interleukin-1β (IL-1β) immunoassay, and the detection of caspase-1 (CAS1). The release of mitochondrial reactive oxygen species (ROS) was also detected. Results: We report here that EMD, like the inflammasome (NLRP3) and CAS1 specific inhibitors—MCC950 and Ac-YVAD-cmk, respectively—lowered the LPS-induced expression of NLRP3 in primary macrophages (EMD: p = 0.0232; MCC950: p = 0.0426; Ac-YVAD-cmk: p = 0.0317). EMD further reduced the LPS-induced expression of NLRP3 in RAW 264.7 cells (p = 0.0043). There was also a reduction in CAS1 and IL-1β in RAW 264.7 macrophages on the transcriptional level (p = 0.0598; p = 0.0283; respectively), in IL-1β protein release (p = 0.0313), and CAS1 activity. Consistently, EMD, like MCC950 and Ac-YVAD-cmk, diminished the ROS release in activated RAW 264.7 cells. In ST2 murine mesenchymal cells, EMD could not be tested because LPS, saliva, and IL-1β + TNF-α failed to provoke pyroptosis signalling. Conclusion: These findings suggest that EMD is capable of dampening the expression of pyroptosis-related genes in macrophages.

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Section: Discussionsupporting

confidence: 93%

Enamel Matrix Derivative Decreases Pyroptosis-Related Genes in Macrophages

Sordi

Cruz

Panahipour

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…In humans, single-nucleotide polymorphisms of the IL1B gene increase susceptibility to periodontitis [ 141 ], and gingival tissues from periodontitis patients show elevated mRNA expression of NLRP3 and IL1B genes [ 142 ]. MCC950 treatment of human periodontal cells in vitro suppressed LPS-dependent cell death and IL-18 and IL-1β secretion [ 143 ]. MCC950 also significantly reduced expression of NLRP3 and Caspase-1 in cell lysates from human periodontal ligament cells [ 143 ].…”

Section: Pathological Roles Of Il-1 In the Skeletonmentioning

confidence: 99%

“…MCC950 treatment of human periodontal cells in vitro suppressed LPS-dependent cell death and IL-18 and IL-1β secretion [ 143 ]. MCC950 also significantly reduced expression of NLRP3 and Caspase-1 in cell lysates from human periodontal ligament cells [ 143 ]. A recent clinical study reported that patients with periodontitis show elevated serum and saliva NLRP3 concentrations [ 144 ], and elevated NLRP3, ASC, and IL-1β concentrations in saliva are proposed biomarkers for periodontal clinical status [ 145 ].…”

Section: Pathological Roles Of Il-1 In the Skeletonmentioning

confidence: 99%

Inflammasomes and the IL-1 Family in Bone Homeostasis and Disease

Tseng

Samuel

Schroder

et al. 2022

Curr Osteoporos Rep

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Purpose of Review Inflammasomes are multimeric protein structures with crucial roles in host responses against infections and injuries. The importance of inflammasome activation goes beyond host defense as a dysregulated inflammasome and subsequent secretion of IL-1 family members is believed to be involved in the pathogenesis of various diseases, some of which also produce skeletal manifestations. The purpose of this review is to summarize recent developments in the understanding of inflammasome regulation and IL-1 family members in bone physiology and pathology and current therapeutics will be discussed. Recent Findings Small animal models have been vital to help understand how the inflammasome regulates bone dynamics. Animal models with gain or loss of function in various inflammasome components or IL-1 family signaling have illustrated how these systems can impact numerous bone pathologies and have been utilized to test new inflammasome therapeutics. Summary It is increasingly clear that a tightly regulated inflammasome is required not only for host defense but for skeletal homeostasis, as a dysregulated inflammasome is linked to diseases of pathological bone accrual and loss. Given the complexities of inflammasome activation and redundancies in IL-1 activation and secretion, targeting these pathways is at times challenging. Ongoing research into inflammasome-mediated mechanisms will allow the development of new therapeutics for inflammasome/IL-1 diseases.

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New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation

kodi,

Sankhe,

Gopinathan

et al. 2024

J Neuroimmune Pharmacol

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Inflammasomes are important modulators of inflammation. Dysregulation of inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related to inflammatory and neurodegenerative diseases. NLRP3 is an intracellular sensor that recognizes pathogen-associated molecular patterns and damage-associated patterns resulting in the assembly and activation of NLRP3 inflammasome. The NLRP3 inflammasome includes sensor NLRP3, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 that plays an imperative role in caspase-1 stimulation which further initiates a secondary inflammatory response. Regulation of NLRP3 inflammasome ameliorates NLRP3-mediated diseases. Much effort has been invested in studying the activation, and exploration of specific inhibitors and epigenetic mechanisms controlling NLRP3 inflammasome. This review gives an overview of the established NLRP3 inflammasome assembly, its brief molecular mechanistic activations as well as a current update on specific and non-specific NLRP3 inhibitors that could be used in NLRP3-mediated diseases. We also focused on the recently discovered epigenetic mechanisms mediated by DNA methylation, histone alterations, and microRNAs in regulating the activation and expression of NLRP3 inflammasome, which has resulted in a novel method of gaining insight into the mechanisms that modulate NLRP3 inflammasome activity and introducing potential therapeutic strategies for CNS disorders. Graphical Abstract "Image missing"

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Targeting the Nod-like receptor protein 3 Inflammasome with inhibitor MCC950 rescues lipopolysaccharide-induced inhibition of osteogenesis in Human periodontal ligament cells

Cited by 6 publications

References 40 publications

Enamel Matrix Derivative Decreases Pyroptosis-Related Genes in Macrophages

Enamel Matrix Derivative Decreases Pyroptosis-Related Genes in Macrophages

Inflammasomes and the IL-1 Family in Bone Homeostasis and Disease

New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation

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