Lentiviral shRNA against KCa3.1 inhibits allergic response in allergic rhinitis and suppresses mast cell activity via PI3K/AKT signaling pathway

Lin, Hai; Zheng, Chenguang; Li, Jing; Yang, Chen; Hu, Li

doi:10.1038/srep13127

Cited by 40 publications

(33 citation statements)

References 45 publications

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“…It might be possible that the reduction of anion secretion also favour apical membrane hyperpolarization, a hypothesis that is supported by the more positive Vte recorded in the Kcnn4 -/-tissue that might be due to Na + accumulation in the mucosa and reduced anion secretion. Besides that, KCa3.1 inhibition has been widely proven by different groups to prevent or ameliorate several inflammatory events including those occurring in the airways (Girodet et al, 2013;Lin et al, 2015;Yu et al, 2017). Since our model is a systemic null-animal other might also participate in the reduction of inflammatory damage after Kcnn4 silencing.…”

Section: Discussionmentioning

confidence: 99%

Lack ofKcnn4improves mucociliary clearance in muco-obstructive lung disease

Vega

Guequén

Philp

et al. 2020

Preprint

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Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping the airways free of infection and mucus obstruction. Airways surface liquid (ASL) volume, ciliary beating and mucus are central for proper MCC, and are critically regulated by sodium (Na + ) absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive disease. The calcium-activated potassium (K + )channel KCa.3.1, encoded by the Kcnn4 gene, participates in intestinal ion secretion and previous studies showed that its activation increase Na + absorption in airway epithelia, suggesting that hyperpolarization induced by KCa3.1 was sufficient to drive Na + absorption.However, its role in airway epithelial function is not fully understood. We therefore aimed to elucidate the role of KCa3.1 in MCC in a genetically engineered mouse model. We show that KCa3.1 inhibition reduced Na + absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency (CBF) and MCC ex vivo and in vivo.Kcnn4 was silenced in the Scnn1b-transgenic mouse (Scnn1b tg/+ ), a model of muco-obstructive lung disease triggered by increased epithelial Na + -absorption, leading to improvements in MCC and reduction of Na + -absorption. KCa3.1 deletion did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1b tg/+ mice. K + -channel modulation may be a novel therapeutic strategy to treat muco-obstuctive lung diseases.

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Section: Discussionmentioning

confidence: 99%

Lack ofKcnn4improves mucociliary clearance in muco-obstructive lung disease

Vega

Guequén

Philp

et al. 2020

Preprint

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“…As the PI3K conformation changes, Ser473 and Thr308 phosphorylation is required for Akt activation (21). A number of previous studies have demonstrated that the PI3K/Akt signaling pathway participated in the regulation of miRNAs on MC degranulation (22)(23)(24). miR-155 controlled MC activation by modulating the PI3Kγ signaling pathway and anaphylaxis in mice with cutaneous anaphylaxis (22).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑126 accelerates IgE‑mediated mast cell degranulation associated with the PI3K/Akt signaling pathway by promoting Ca2+ influx

et al. 2018

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Mast cells (MCs) have been reported to serve a crucial role in allergic diseases, including asthma, allergic rhinitis and anaphylaxis. A previous study revealed that microRNA-126 (miR-126) was associated with airway hyperresponsiveness induced by house dust mites, however the molecular mechanisms were unclear. The present study aimed to investigate the effect of miR-126 on immunoglobulin E (IgE)-regulated MC degranulation and explore its underlying mechanisms. miR-126 expression was quantified using a rat model and in rat peritoneal mast cells (RPMCs). Overexpression or downregulation of miR-126 was established by transfection with miR-126 mimics or miR-126 inhibitors and MC degranulation was subsequently evaluated. The effect of miR-126 on protein kinase B (Akt) and phosphorylated Akt protein expression was examined by western blot analysis. The phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) was used to determine the role of the PI3K/Akt signaling pathway. In addition, cytosolic calcium (Ca) levels were measured by a fura-2 assay. The results demonstrated that miR-126 expression was upregulated in the ear tissues of rats with allergic contact dermatitis and IgE-activated MCs. The overexpression of miR-126 in RPMCs was established following miR-126 mimic transfection. The release of β-hexosaminidase and histamine, markers of MC degranulation, were significantly increased in cells with miR-126 overexpression. The phosphorylation of Akt was significantly increased following transfection with miR-126 mimics in stimulated cells, however the signaling activation was abrogated by LY294002. In addition, Ca influx was significantly promoted in stimulated RPMCs overexpressing miR-126. These results indicate that miR-126 accelerated IgE-mediated MC degranulation associated with the PI3K/Akt signaling pathway by promoting Ca influx. This suggests that miR-126 may be a promising therapeutic target for the treatment of allergic skin diseases.

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“…In addition, IL-8 expression has been shown to be regulated by the PI3K/AKT signaling pathway [65]. The PI3K/AKT signaling pathway also plays a key role in the IgE-mediated maturation and activation of mast cells [66,67]. The suppression of the PI3K/AKT signaling pathway has been reported to lead to the inhibition of TNF-α-induced inflammation [68].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-200a Affects the Proliferation of Airway Smooth Muscle Cells and Airway Remodeling by Targeting FOXC1 via the PI3K/AKT Signaling Pathway in Ovalbumin-Induced Asthmatic Mice

Liu¹,

Miao²,

Gào³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The etiology of asthma, which is a complicated disorder with various symptoms, including wheezing, coughing, and airflow obstruction, remains poorly understood. In addition, the effects of microRNAs (miRs) have not been explored. This study explored the effect of microRNA-200a (miR-200a) on airway smooth muscle cells (ASMCs) and airway remodeling in asthmatic mice. Furthermore, we speculated that miR-200a achieves its effect by targeting FOXC1 via the PI3K/AKT signaling pathway based on differentially expressed gene screening, target miR predictions and a bioinformatics analysis. Methods: Eighty mice were assigned to a saline group or an ovalbumin (OVA) group, and the OVA group was transfected with a series of inhibitors, activators, and siRNAs to test the established mouse model. Airway reactivity and the ratio of eosinophils (EOSs) to leukocytes were detected. An ELISA was adopted to measure the levels of interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor (TNF)-α, and immunoglobulin E (IgE). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to determine the expression of FOXC1, PI3K, AKT, NF-κB, cyclin D1, TGF-β1 and p-AKT in ASMCs. Finally, CCK-8 assays were performed to detect cell proliferation and flow cytometry to detect apoptosis and cell cycle entry. Results: The bioinformatics analysis indicated that miR-200a mediated the PI3K/AKT signaling pathway by targeting FOXC1. In addition, mouse models of asthma were established. An elevated expression of miR-200a, a decreased mRNA and protein expression of FOXC1, PI3K, AKT, NF-κB, cyclin D1 and TGF-β1, a decreased expression of p-AKT, suppressed cell proliferation, accelerated apoptosis, and an increased number of cells at the G0/G1 phase were observed following the upregulation of miR-200a and downregulation of FOXC1. Conclusion: The overexpression of miR-200a may downregulate FOXC1, thereby inhibiting the activation of the PI3K/AKT signaling pathway and ultimately suppressing ASMC proliferation and airway remodeling in asthmatic mice. This evidence supports the potential that miR-200a represents a new approach to treating asthma.

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Lentiviral shRNA against KCa3.1 inhibits allergic response in allergic rhinitis and suppresses mast cell activity via PI3K/AKT signaling pathway

Cited by 40 publications

References 45 publications

Lack ofKcnn4improves mucociliary clearance in muco-obstructive lung disease

Lack ofKcnn4improves mucociliary clearance in muco-obstructive lung disease

MicroRNA‑126 accelerates IgE‑mediated mast cell degranulation associated with the PI3K/Akt signaling pathway by promoting Ca2+ influx

MicroRNA-200a Affects the Proliferation of Airway Smooth Muscle Cells and Airway Remodeling by Targeting FOXC1 via the PI3K/AKT Signaling Pathway in Ovalbumin-Induced Asthmatic Mice

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