Toll‑like receptor 4 activates the NLRP3 inflammasome pathway and periodontal inflammaging by inhibiting Bmi‑1 expression

Qin, Ziyue; Gu, Xiaohong; Chen, Yulian; Liu, Jia‐Bao; Hou, Chen‐Xing; Lin, Shiyu; Hao, Nannan; Liang, Yan; Wu, Chunxiao; Meng, Haoyu

doi:10.3892/ijmm.2020.4787

Cited by 30 publications

(23 citation statements)

References 45 publications

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“…Previous studies have noted that the periodontal cells of diabetic mice experience a chronic, low‐degree inflammatory state termed inflamm‐aging, characterized by cell senescence and SASP secretion (Qin et al, 2020; Wang et al, 2020). We have observed that p16 and p21 expressions are significantly increased in periodontal cells of diabetic mice, in agreement with previous reports.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

Zhao

Yue

Nie

et al. 2021

J Clinic Periodontology

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Aim: Pyroptosis and inflamm-aging have been newly identified to be involved in diabetic periodontitis. This study aimed to elucidate whether macrophage pyroptosis plays a role in periodontal inflamm-aging by impacting the senescence of fibroblasts, as well as the potential mechanism via NLR family CARD domain-containing protein 4 (NLRC4) phosphorylation.Materials and methods: Diabetes was induced in mice using streptozotocin. Periodontal pyroptosis and senescence were detected using immunohistochemical analysis. Prior to evaluating senescence in human gingival fibroblasts cultured with conditioned medium derived from macrophages, RAW 264.7 macrophages were confirmed to undergo pyroptosis by scanning electron microscopy and gasdermin D (GSDMD) detection. The NLRC4-related pathway was examined under hyperglycaemic conditions.Results: Our data showed that macrophage pyroptosis induced the expression of senescent markers in vivo and in vitro. Importantly, clearance of pyroptotic macrophages rescued senescence in fibroblasts. Furthermore, GSDMD activation and pyroptosis in hyperglycaemia were found to be mediated by NLRC4 phosphorylation.Conclusions: Hyperglycaemia could initially induce macrophage pyroptosis and lead to cellular senescence, thereby critically contributing to periodontal pathogenesis in diabetes. In particular, NLRC4 phosphorylation could be a potential therapeutic target for the inhibition of this process.

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Section: Discussionmentioning

confidence: 99%

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

Zhao

Yue

Nie

et al. 2021

J Clinic Periodontology

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“…Periodontitis (PD) in adults is a chronic inflammatory disease of ageing or inflammaging ( Ebersole et al., 2018 ; Qin et al., 2020 ). This is particularly striking when the National Health and Nutrition Examination Survey (NHANES) data from 2009-2010 are stratified by patient age, with PD prevalence increasing from 24.4% in adults aged 30-34 yrs., to 70.1% in those aged 65 yrs.…”

Section: Introductionmentioning

confidence: 99%

Porphyromonas gingivalis Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells

Elsayed

Elashiry

Liu

et al. 2021

Front. Cell. Infect. Microbiol.

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Periodontitis is a disease of ageing or inflammaging, and is comorbid with other more severe age-related chronic diseases. With advanced age comes an increase in accumulation of senescent cells that release soluble and insoluble pro-inflammatory factors collectively termed the senescence associated secretory phenotype (SASP). In the present report, we examined whether immune cells typical of those at the oral mucosa-microbe interface, are vulnerable to cellular senescence (CS) and the role of dysbiotic oral pathogen Porphyromonas gingivalis. Bone marrow-derived dendritic cells (DCs) from young (yDCs) and old (oDCs) mice were co-cultured in vitro with CS inducer doxorubicin or P.gingivalis (Pg), plus or minus senolytic agent rapamycin. CS profiling revealed elevated CS mediators SA-β-Gal, p16 INK4A, p53, and p21Waf1/Clip1 in oDCs, or yDCs in response to doxorubicin or P. gingivalis, reversible with rapamycin. Functional studies indicate impaired maturation function of oDCs, and yDC exposed to P. gingivalis; moreover, OVA-driven proliferation of CD4+ T cells from young OTII transgenic mice was impaired by oDCs or yDCs+Pg. The SASP of DCs, consisting of secreted exosomes and inflammasome-related cytokines was further analyzed. Exosomes of DCs cocultured with P. gingivalis (PgDCexo) were purified, quantitated and characterized. Though typical in terms of size, shape and phenotype, PgDCexo were 2-fold greater in number than control DCs, with several important distinctions. Namely, PgDCexo were enriched in age-related miRNAs, and miRNAs reported to disrupt immune homeostasis through negative regulation of apoptosis and autophagy functions. We further show that PgDCexo were enriched in P. gingivalis fimbrial adhesin protein mfa1 and in inflammasome related cytokines IL-1β, TNFα and IL-6. Functionally PgDCexo were readily endocytosed by recipient yDCs, amplifying functional impairment in maturation and ability to promote Ova-driven proliferation of OTII CD4+ T cells from young mice. In conclusion P. gingivalis induces premature (autocrine) senescence in DCs by direct cellular invasion and greatly amplifies senescence, in paracrine, of bystander DCs by secretion of inflammatory exosomes. The implications of this pathological pathway for periodontal disease in vivo is under investigation in mouse models.

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“…Pyroptosis is closely associated with the development of atherosclerosis, referring to pyroptosis in endothelial cells and macrophages [14]. The NLRP3 inflammasome is one of the major sources of inflammation in age-related diseases [15]. Several types of inflammasome were notably activated in the ageing kidneys of rats [16].…”

Section: Introductionmentioning

confidence: 99%

Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

Wada

Umeno

Nagasu

et al. 2021

IJMS

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Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

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Toll‑like receptor 4 activates the NLRP3 inflammasome pathway and periodontal inflammaging by inhibiting Bmi‑1 expression

Cited by 30 publications

References 45 publications

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

Hyperglycaemia‐associated macrophage pyroptosis accelerates periodontal inflamm‐aging

Porphyromonas gingivalis Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells

Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

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