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NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-?B signaling.

ABSTRACT: Inflammatory bowel disease (IBD) is one of the most common diseases in the gastrointestinal tract related to aberrant inflammation. Pyroptosis, which is characterized by inflammasome formation, the activation of caspase-1, and the separation of the N- and C-terminals of GSDMD, might be related to IBD pathogenesis. NEK7 is an important component of the NLRP3 inflammasome in macrophages. We attempted to investigate the mechanism of NEK7 interacting with NLRP3 to modulate the pyroptosis in IBD. NEK7 mRNA and protein expression and pyroptosis-associated factors, including Caspase-1 (p45, p20), NLRP3, and GSDMD, were upregulated in IBD tissues. NEK7 knockdown abolish ATP?+?LPS-induced pyroptosis in vitro and improved DSS-induced chronic colitis in vivo. NEK7 interacted with NLRP3, as revealed by Co-IP and GST pull-down assays, to exert its effects. Moreover, short-term LPS treatment alone induced no significant changes in NEK7 protein level. TLR4/NF-?B signaling in MODE-K cells could be activated by LPS treatment. LPS-induced NEK7 upregulation could be significantly reversed by JSH-23, an inhibitor of p65. Furthermore, LUC and ChIP assays revealed that RELA might activate the transcription of NEK7 via targeting its promoter region. LPS-induced TLR4/NF-?B activation causes an increase in NEK7 expression by RELA binding NEK7 promoter region. In conclusion, NEK7 interacts with NLRP3 to modulate NLRP3 inflammasome activation, therefore modulating the pyroptosis in MODE-K cells and DSS-induced chronic colitis in mice. We provide a novel mechanism of NEK7-NLRP3 interaction affecting IBD via pyroptosis.

SUBMITTER: Chen X

PROVIDER: S-EPMC6885517 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling.

Chen Xueliang X Liu Ganglei G Yuan Yuanyuan Y Wu Guotao G Wang Shalong S Yuan Lianwen L

Cell death & disease 20191202 12

Inflammatory bowel disease (IBD) is one of the most common diseases in the gastrointestinal tract related to aberrant inflammation. Pyroptosis, which is characterized by inflammasome formation, the activation of caspase-1, and the separation of the N- and C-terminals of GSDMD, might be related to IBD pathogenesis. NEK7 is an important component of the NLRP3 inflammasome in macrophages. We attempted to investigate the mechanism of NEK7 interacting with NLRP3 to modulate the pyroptosis in IBD. NEK ...[more]

PMID: 31787755

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Project description:BackgroundPicroside II (P-II) is the main bioactive constituent of Picrorhiza Kurroa, a traditional Chinese herb of interest for its proven anti-inflammatory properties. Its beneficial effects have been noted across several physiological systems, including the nervous, circulatory, and digestive, capable of treating a wide range of diseases. Nevertheless, the potential of Picroside II to treat osteoarthritis (OA) and the mechanisms behind its efficacy remain largely unexplored.AimThis study aims to evaluate the efficacy of Picroside II in the treatment of osteoarthritis and its potential molecular mechanisms.MethodsIn vitro, we induced cellular inflammation in chondrocytes with lipopolysaccharide (LPS) and subsequently treated with Picroside II to assess protective effect on chondrocyte. We employed the Cell Counting Kit-8 (CCK-8) assay to assess the impact of Picroside II on cell viability and select the optimal Picroside II concentration for subsequent experiments. We explored the effect of Picroside II on chondrocyte pyroptosis and its underlying molecular mechanisms by qRT-PCR, Western blot (WB) and immunofluorescence. In vivo, we established the destabilization of the medial meniscus surgery to create an OA mouse model. The therapeutic effects of Picroside II were then assessed through Micro-CT scanning, Hematoxylin-eosin (H&E) staining, Safranin O-Fast Green (S&F) staining, immunohistochemistry and immunofluorescence.ResultsIn in vitro studies, toluidine blue and CCK-8 results showed that a certain concentration of Picroside II had a restorative effect on the viability of chondrocytes inhibited by LPS. Picroside II notably suppressed the expression levels of caspase-1, IL-18, and IL-1β, which consequently led to the reduction of pyroptosis. Moreover, Picroside II was shown to decrease NLRP3 inflammasome activation, via the MAPK/NF-κB signaling pathway. In vivo studies have shown that Picroside II can effectively reduce subchondral bone destruction and osteophyte formation in the knee joint of mice after DMM surgery.ConclusionsOur research suggests that Picroside II can inhibit chondrocyte pyroptosis and ameliorate osteoarthritis progression by modulating the MAPK/NF-κB signaling pathway.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is a highly lethal malignancy with poor prognosis. Polypeptide N-acetylgalactosaminyltransferase-6 (GALNT6) is frequently overexpressed in PDAC. However, the role of GALNT6 in the PDAC remains unclear.MethodsThe expression of GALNT6 in pancreatic cancer and normal tissues were analyzed by bioinformatic analyses and immunohistochemistry. CCK8 and colony formation were used to detect cell proliferation. Flow cytometry was applied to detect cell cycle.The pyroptosis was detected by scanning electron microscopy. The mRNA expression was detected by qRT-PCR. The protein expression and localization were detected by western blot and immunofluorescence assay. ELISA was used to detect the levels of inflammatory factors.ResultsThe expression of GALNT6 was associated with advanced tumor stage, and had an area under curve (AUC) value of 0.919 in pancreatic cancer based on the cancer genome atlas (TCGA) dataset. Knockdown of GALNT6 inhibited cell proliferation, migration, invasion and cell cycle arrest of PDAC cells. Meanwhile, knockdown of GALNT6 increased the expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18), the release of inflammasome and an increasing of Gasdermin D (GSDMD), N-terminal of GSDMD (GSDMD-N), Gasdermin E (GSDME) and N-terminal of GSDME (GSDME-N) in PDAC cells. GALNT6 suppressed the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and GSDMD by glycosylation of NF-κB and inhibiting the nucleus localization of NF-κB. Additionally, GALNT6 promotes the degradation of GSDME by O-glycosylation.ConclusionWe found that GALNT6 is highly expressed in pancreatic cancer and plays a carcinogenic role. The results suggested that GALNT6 regulates the pyroptosis of PDAC cells through NF-κB/NLRP3/GSDMD and GSDME signaling. Our study might provides novel insights into the roles of GALNT6 in PDAC progression.

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NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-?B signaling.

Publications

NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling.

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