TNF-α–Induced miR-21-3p Promotes Intestinal Barrier Dysfunction by Inhibiting MTDH Expression

Jiang, Zhongnong; Fei-yu, Yang; Qie, Jingbo; Jin, Chaoyuan; Zhang, Feng; Shen, Jie; Zhang, Lin

doi:10.3389/fphar.2021.722283

Cited by 6 publications

(5 citation statements)

References 32 publications

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“…In recent years, a limited number of studies also confirmed that AEG-1 may be associated with barrier dysfunction. Jiang et al [26] found that upon TNF-a stimulation of CaCo2 cells, miR-21-3p expression was elevated, which directly targeted AEG-1 mRNA, consequently modulating intestinal barrier dysfunction. Another study revealed that inhibiting AEG-1 and its downstream pro-inflammatory cytokines mitigated blood-spinal cord barrier leakage and improved hind limb motor function during spinal cord ischemia-reperfusion [27].…”

Section: Discussionmentioning

confidence: 99%

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Jiang,

Wang,

et al. 2024

Aids

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Objective: This study aims to investigate the functions and mechanistic pathways of Astrocyte Elevated Gene-1 (AEG-1) in the disruption of the blood–retinal barrier (BRB) caused by the HIV-1 envelope glycoprotein gp120. Design: We utilized ARPE-19 cells challenged with gp120 as our model system. Methods: Several analytical techniques were employed to decipher the intricate interactions at play. These included PCR, Western blot, and immunofluorescence assays for the molecular characterization, and transendothelial electrical resistance (TEER) measurements to evaluate barrier integrity. Results: We observed that AEG-1 expression was elevated, whereas the expression levels of tight junction proteins Zo-1, Occludin, and Claudin5 were downregulated in gp120-challenged cells. TEER measurements corroborated these findings, indicating barrier dysfunction. Additional mechanistic studies revealed that the activation of NFκB and MMP2/9 pathways mediated the AEG-1-induced barrier destabilization. Through the use of lentiviral vectors, we engineered cell lines with modulated AEG-1 expression levels. Silencing AEG-1 alleviated gp120-induced downregulation of tight junction proteins and barrier impairment while concurrently inhibiting the NFκB and MMP2/9 pathways. Conversely, overexpression of AEG-1 exacerbated these pathological changes, further compromising the integrity of the BRB. Conclusion: Gp120 upregulates the expression of AEG-1 and activates the NFκB and MMP2/9 pathways. This in turn leads to the downregulation of tight junction proteins, resulting in the disruption of barrier function.

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Section: Discussionmentioning

confidence: 99%

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Jiang,

Wang,

et al. 2024

Aids

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“…Although the underlying mechanism through which MG infection leads to TJ damage has not yet been fully elucidated, some studies have shown a close correlation between the suppression of TJ protein expression and an increase in proinflammatory mediators [ 41 ]. Jiang et al discovered that TNF-α acts as another key cytokine that coordinates tracheal epithelial damage in the context of MG infection and can activate the NF-κB pathway [ 42 ]. Growing evidence suggests that when exposed to pathogenic agents, the trachea experiences an increase in intracellular calcium ion levels.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory responses and barrier disruption in the trachea of chicks following Mycoplasma gallisepticum infection: a focus on the TNF-α-NF-κB/MLCK pathway

Zhong,

Wu,

Zhao

et al. 2024

Vet Res

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Mycoplasma gallisepticum (MG) can induce persistent inflammatory damage to the tracheal mucosa of poultry and cause chronic respiratory diseases in chickens. To further investigate the mechanism of MG-induced injury to the tracheal mucosa, we used chick embryo tracheal organ culture (TOC) as a model to study the invasion and reproduction of MG, the effect of MG on tracheal morphology, and the potential factors that promote MG tissue invasion. The results showed that MG infection significantly damaged the tracheal epithelial structure and weakened tracheal epithelial barrier function; MG also increased the occurrence of bacterial displacement, with a significant (p < 0.05) increase in the bacterial load of the infected TOCs at 5 and 7 days post-infection. In addition, MG significantly (p < 0.05) increased the expression levels of inflammatory cytokines, such as TNF-α, interleukin-1β (IL-1β), and IL-6, and activated the NF-κB signalling pathway, leading to increased nuclear translocation of NF-κB p65. Simultaneously, the map kinase pathway (MAPK) was activated. This activation might be associated with increased myosin light chain (MLC) phosphorylation, which could lead to actin-myosin contraction and disruption of tight junction (TJ) protein function, potentially compromising epithelial barrier integrity and further catalysing MG migration into tissues. Overall, our results contribute to a better understanding of the interaction between MG and the host, provide insight into the mechanisms of damage to the tracheal mucosa induced by MG infection, and provide new insights into the possible pathways involved in Mycoplasma gallisepticum infection in vivo.

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“…MiRNA-21-3p has been recently shown to play a role in the regulation of the expression of tight junction proteins responsible for the integrity of the intestinal epithelial barrier in the GIT. A recent 2021 study demonstrates that TNF-α-induced expression of miRNA-21-3p caused decreased levels of metadherin (MTDH) [72]. MTDH is a negative regulator of the Wnt signalling pathway.…”

Section: Tnf-α/ Wnt Signalling Pathway As a Regulator Of Intestinal B...mentioning

confidence: 99%

MiRNA-21 Regulates Multiple Factors in the Pathogenesis of IBD: A Literature Review

2023

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Introduction: Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract (GIT) via dysbiosis of the gut microbiome and weakening of the epithelial and mucosal barriers. Although the causative nature of IBD remains unknown, several studies have demonstrated that aberrant host-microRNA (miRNA) activity contributes to its pathophysiology. For example, miRNA-21 contributes to IBD through three mechanisms. Firstly, by increasing gut permeability via the ARF4 pathway. Secondly, by decreasing gut mucosal secretions via interfering with host goblet cells. Finally, by regulating proteins that inhibit host autophagy and decreasing immune response via the Phosphatase and Tensin Homolog (PTEN) and Akt pathway. The proposed study aims to answer the following question: how does aberrant expression of miRNA-21 in IBD contribute to the disease? Methods: This review highlights and summarizes relevant studies on the miRNA-21 regulation of key pathways in the pathogenesis of IBD. Searches used electronic databases including PubMed, and Google Scholar for keywords such as "Inflammatory bowel disease" and "miRNA-21" and other additional relevant terms from years 2016 to 2022. Review papers that met our criteria and the relevant papers they referenced, regardless of their publication date, were manually searched for. Figures were made in part using KeyNote and Serveir Medical Art. Discussion: Intracellular pathways contribute to chronic inflammation in IBD such as the PTEN pathway and proinflammatory cytokines like TNF-α. These pathways have been shown to influence the mucosal barrier, epithelial barrier, and the immune system in the gut. These pathways are regulated by miRNA-21, demonstrating miRNA-21 as a key regulator in IBD. Both PTEN and TNF-α also contribute to levels of angiogenesis in the gut through the regulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF), further demonstrating the intricacies of the miRNA-21 pathway regulation in IBD. Conclusion:The research highlighted in this review provides insight into the mechanisms of aberrant miRNA expression in IBD. Furthermore, knowledge of such molecular mechanisms has clinical and research applications, including identifying diagnostic biomarkers, less invasive screening techniques, and novel drug therapies.

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TNF-α–Induced miR-21-3p Promotes Intestinal Barrier Dysfunction by Inhibiting MTDH Expression

Cited by 6 publications

References 32 publications

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Inflammatory responses and barrier disruption in the trachea of chicks following Mycoplasma gallisepticum infection: a focus on the TNF-α-NF-κB/MLCK pathway

MiRNA-21 Regulates Multiple Factors in the Pathogenesis of IBD: A Literature Review

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