Butyrate rather than LPS subverts gingival epithelial homeostasis by downregulation of intercellular junctions and triggering pyroptosis

Liu, Juan; Wang, Yixiang; Meng, Hua; Yu, Jenwei; Lu, Hongye; Li, Wenjing; Lu, Ruifang; Zhao, Yibing; Li, Qiqiang; Su, Li

doi:10.1111/jcpe.13162

Cited by 55 publications

(73 citation statements)

References 59 publications

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“…Such features are all observed in our experiment, and we also observed dampened GPx4 expression but elevated ASL4 expression, which further suggest the onset of ferroptosis. Since butyrate can trigger apoptosis, pyroptosis, and autophagic cell death in gingival epithelial cells and fibroblasts 9,36,37 . Moreover, butyrate rather than LPS compromised the gingival epithelial barrier by triggering pyroptosis 9 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, periodontitis-level butyrate plays a detrimental role in the periodontal tissues. It may inhibit fibroblast cell growth and proliferation, elicit oxidative stress as well as endoplasmic reticulum stress 8 , pyroptosis 9 , and apoptosis 10 . Although the periodontal ligament fibroblasts (PDLFs) can maintain the homeostasis of periodontal ligament through its proliferation and differentiation, persistent detrimental stimuli may lead to irreversible loss of the resident PDLFs.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the non-inflammatory apoptosis, several types of regulated cell death (RCD) have been well recognized, such as apoptosis, pyroptosis, NETosis, and necroptosis. Apoptosis is reduced in diseased periodontal tissues 12 , while pyroptosis and necroptosis are increased in inflamed periodontal tissues 9,13 .…”

Section: Introductionmentioning

confidence: 99%

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Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

Zhao

Guo

et al. 2020

Cell Death Discov.

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Loss of periodontal ligament fibroblasts (PDLFs) is one critical issue for regenerating lost periodontal tissues. A wide variety of regulated cell death pathways, such as apoptosis, pyroptosis, and necroptosis have been proposed in the periodontitis development. The aim of the present study was to explore whether long-term periodontitis-level butyrate may trigger ferroptosis, a newly characterized iron-dependent regulated cell death in PDLFs. Here, we showed that long-term treatment of butyrate, an important short-chain fatty acid in the periodontal pocket, induces the cargo receptor nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis in PDLFs. Butyrate-induced iron accumulation, reactive oxygen species (ROS) generation, glutathione depletion and lipid peroxidation in PDLFs, and the butyrate-induced ferroptosis can be blocked by the lipid peroxide scavenger ferrostatin-1. The NCOA4-mediated ferritinophagy is dependent on p38/hypoxia inducible factor-1α (HIF-1α) pathway activation as well as Bromodomain-containing protein (BRD) 4 and cyclin-dependent kinase 9 (CDK9) coordination. These lines of evidence provide a new mechanistic insight into the mechanism of loss of PDLFs during periodontitis development, showing that periodontitis-level butyrate disrupted iron homeostasis by activation of NCOA4-mediated ferritinophagy, leading to ferroptosis in PDLFs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

Zhao

Guo

et al. 2020

Cell Death Discov.

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“…Furthermore, abnormal accumulation of atRAL activates NLRP3 inflammasome to promote the death of RPE cells due to a significant increase in the proportion of human ARPE-19 cells exhibiting features of caspase3/GSDME-mediated pyroptosis [72]. Sodium butyrate breaks down cell-cell junctions and triggers caspase3/GSDME-dependent pyroptosis in the gingival epithelial cells to destroy the epithelial barrier and shed a new light on our understanding of periodontitis initiation [73]. GSDME-mediated pyroptosis is poorly studied in inflammatory disease.…”

Section: Other Ways To Regulate Pyroptosis Involved In Inflammatory Dmentioning

confidence: 99%

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

Zheng

2020

IJMS

146

111

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Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.

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“…The presence of SCFA in the infectious site attenuates the neutrophils response to A. actinomycetemcomitans as a result of the inhibition of specific isoforms of HDACs, namely, HDAC 1 and 3, but not activation of FFAR2 [31]. Recent findings suggest that butyrate disturbs gingival epithelial homeostasis and initiates expression of pro-inflammatory cytokine in vitro [32]. Thus, there is accumulating evidence suggesting that SCFA has detrimental effects on cells of the periodontium.…”

mentioning

confidence: 99%

Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells

Magrin

Summa

Strauß

et al. 2020

IJMS

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Short-chain fatty acids (SCFA) are bacterial metabolites that can be found in periodontal pockets. The expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) within the epithelium pocket is considered to be a key event for the selective transmigration of leucocytes towards the gingival sulcus. However, the impact of SCFA on ICAM-1 expression by oral epithelial cells remains unclear. We therefore exposed the oral squamous carcinoma cell line HSC-2, primary oral epithelial cells and human gingival fibroblasts to SCFA, namely acetate, propionate and butyrate, and stimulated with known inducers of ICAM-1 such as interleukin-1-beta (IL1β) and tumor necrosis factor-alfa (TNFα). We report here that butyrate but not acetate or propionate significantly suppressed the cytokine-induced ICAM-1 expression in HSC-2 epithelial cells and primary epithelial cells. The G-protein coupled receptor-43 (GPR43/ FFAR2) agonist but not the histone deacetylase inhibitor, trichostatin A, mimicked the butyrate effects. Butyrate also attenuated the nuclear translocation of p65 into the nucleus on HSC-2 cells. The decrease of ICAM-1 was independent of Nrf2/HO-1 signaling and phosphorylation of JNK and p38. Nevertheless, butyrate could not reverse an ongoing cytokine-induced ICAM-1 expression in HSC-2 cells. Overall, these observations suggest that butyrate can attenuate cytokine-induced ICAM-1 expression in cells with epithelial origin.Int. J. Mol. Sci. 2020, 21, 1679 2 of 15 crevicular fluid by means of a tightly controlled expression of adhesion molecules, thereby defending microbiological antagonism in the periodontal tissue [2,3]. Thus, the increase of adhesion molecules by inflammatory mediators has to be counterbalanced by local cues to control an excessive influx of cells of the innate immune system.The influx of cells is controlled by intercellular adhesion molecule-1 (ICAM-1), allowing the transmigration of leucocytes which express the corresponding lymphocyte function-associated antigen-1 and macrophage adhesion ligand-1 [4]. ICAM-1, being induced by inflammatory cues such as interleukin-1-beta (IL1β) and tumor necrosis factor-α (TNFα) [5], is expressed by the vascular endothelium and by the junctional epithelium [6], thus, facilitating transmigration of leukocytes across vascular endothelia and the invasion of the extracellular matrix [7]. Although ICAM-1 is consistently expressed by junctional epithelial cells in healthy gingiva and in pocket epithelium, it is not detectable on the majority of keratinocytes in the external gingival epithelium [6,8]. The question then arises, how is the expression of ICAM-1 in epithelial cells controlled?The increase of ICAM-1 expression by inflammatory cues is evidently well-documented. Inflammatory mediators including IL-6 and prostaglandin E 2 increase ICAM-1 expression in human oral squamous cell carcinoma SCC4 cells in vitro [9,10]. Primary gingival epithelial cells increasingly express ICAM-1 upon inflammatory cytokines stimuli, namely, TNFα and interferon-γ [11]....

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Butyrate rather than LPS subverts gingival epithelial homeostasis by downregulation of intercellular junctions and triggering pyroptosis

Cited by 55 publications

References 59 publications

Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells

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