Long non‐coding RNA MEG3 inhibits M2 macrophage polarization by activating TRAF6 via microRNA‐223 down‐regulation in viral myocarditis

Xue, Yulong; Zhang, Sheng‐Xiao; Zheng, Chunhua; Li, Yufeng; Zhang, Lihui; Su, Q. Y.; Hao, Yu‐Fei; Wang, Shu; Li, Xue‐Wen

doi:10.1111/jcmm.15720

Cited by 51 publications

(56 citation statements)

References 49 publications

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“…We next sought to identify the MFG-E8-derived pathways responsible for chondrocyte senescence and macrophage reprogramming during OA. The NF-κB pathway is a well explored inflammatory pathway, which is over-activated in OA, exacerbating chondrocyte matrix degradation, synovial inflammation, and macrophage M1 polarization 21 , 22 . Excitingly, we found that MFG-E8 treatment rescued the phosphorylation of p65 NF-κB signaling, while neutralizing MFG-E8 significantly enhanced p65 phosphorylation both in cartilage and in synovium post OA surgery (Fig.…”

Section: Resultsmentioning

confidence: 99%

MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway

Liu

Pan

et al. 2021

Cell Death Dis

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Milk fat globule-epidermal growth factor (EGF) factor 8 (MFG-E8), as a necessary bridging molecule between apoptotic cells and phagocytic cells, has been widely studied in various organs and diseases, while the effect of MFG-E8 in osteoarthritis (OA) remains unclear. Here, we identified MFG-E8 as a key factor mediating chondrocyte senescence and macrophage polarization and revealed its role in the pathology of OA. We found that MFG-E8 expression was downregulated both locally and systemically as OA advanced in patients with OA and in mice after destabilization of the medial meniscus surgery (DMM) to induce OA. MFG-E8 loss caused striking progressive articular cartilage damage, synovial hyperplasia, and massive osteophyte formation in OA mice, which was relieved by intra-articular administration of recombinant mouse MFG-E8 (rmMFG-E8). Moreover, MFG-E8 restored chondrocyte homeostasis, deferred chondrocyte senescence and reprogrammed macrophages to the M2 subtype to alleviate OA. Further studies showed that MFG-E8 was inhibited by miR-99b-5p, expression of which was significantly upregulated in OA cartilage, leading to exacerbation of experimental OA partially through activation of NF-κB signaling in chondrocytes. Our findings established an essential role of MFG-E8 in chondrocyte senescence and macrophage reprogramming during OA, and identified intra-articular injection of MFG-E8 as a potential therapeutic target for OA prevention and treatment.

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Section: Resultsmentioning

confidence: 99%

MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway

Liu

Pan

et al. 2021

Cell Death Dis

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“…The expression of miR-223 is regulated by three transcription factors, namely C/EBPα, PU.1, and NFI-A [ 48 ], and there is not any direct evidence that EP affects these transcription factors. On the other hand, EP may alter miR-223 expression through indirect mechanisms, such as long-non-coding RNAs (lncRNAs) and Nrf2 signaling pathway [ 49 , 50 , 51 , 52 ]. Some lncRNAs, such as GAS5, DLX6-AS1, and MEG3, have been reported to modulate miR-223 expression [ 49 , 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, EP may alter miR-223 expression through indirect mechanisms, such as long-non-coding RNAs (lncRNAs) and Nrf2 signaling pathway [ 49 , 50 , 51 , 52 ]. Some lncRNAs, such as GAS5, DLX6-AS1, and MEG3, have been reported to modulate miR-223 expression [ 49 , 50 , 51 ]. The Nrf2 signaling pathway is the main antioxidant signaling pathway under the stress condition, and overexpression of Nrf2 upregulates miR-223 expression [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Ethyl Pyruvate Attenuates Microglial NLRP3 Inflammasome Activation via Inhibition of HMGB1/NF-κB/miR-223 Signaling

et al. 2021

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Ethyl pyruvate is a molecule with anti-inflammatory and pro-metabolic effects. Ethyl pyruvate has been shown to ameliorate the clinical and pathological findings of neurodegenerative diseases such as Alzheimer’s and Parkinson’s Diseases in rodents. Its anti-inflammatory and neuroprotective effects are widely investigated in animal and cellular models. Our study aimed to investigate the mechanism of the impact of Ethyl pyruvate on NLRP3 inflammasome activation in the N9 microglial cell line. Our results indicated that ethyl pyruvate significantly suppressed LPS and ATP-induced NLRP3 inflammasome activation, decreased active caspase-1 level, secretion of IL-1β and IL-18 cytokines, and reduced the level of pyroptotic cell death resulting from inflammasome activation. Furthermore, ethyl pyruvate reduced the formation of total and mitochondrial ROS and suppressed inflammasome-induced HMGB1 upregulation and nuclear NF-κB translocation and reversed the inflammasome activation-induced miRNA expression profile for miR-223 in N9 cells. Our study suggests that ethyl pyruvate effectively suppresses the NLRP3 inflammasome activation in microglial cells regulation by miR-223 and NF-κB/HMGB1 axis.

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“…The lncRNA MEG3 was initially found to be a tumor suppressor that can inhibit the proliferation of tumor cells ( Benetatos et al, 2011 ), but has also been found recently to regulate pyroptosis ( Zhang Y. et al, 2018 ; Liang et al, 2020 ; Zou et al, 2020 ). Multiple studies have shown that MEG3 is involved in regulating inflammatory-response mechanisms in various diseases such as acute pancreatitis ( Xue et al, 2020 ), chronic obstructive pulmonary disease ( Lei et al, 2021 ), and ultraviolet skin injury ( Zhang et al, 2019 ). Disrupting the expression of MEG3 can reduce the production of inflammatory factors via various pathways.…”

Section: Discussionmentioning

confidence: 99%

Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury

et al. 2021

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Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI.Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1β and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1β, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment.Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1β, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis.Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.

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Long non‐coding RNA MEG3 inhibits M2 macrophage polarization by activating TRAF6 via microRNA‐223 down‐regulation in viral myocarditis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 51 publications

References 49 publications

MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway

MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway

Ethyl Pyruvate Attenuates Microglial NLRP3 Inflammasome Activation via Inhibition of HMGB1/NF-κB/miR-223 Signaling

Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury

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