Calpain‐activated mTORC2/Akt pathway mediates airway smooth muscle remodelling in asthma

Rao, Shobha; Mu, Qing; Zeng, Yu; Cai, Peng; Liu, Fei; Yang, Jie; Xia, Yu; Zhang, Qian; Song, Linjie; Zhou, Linlin; Li, Feng‐Zhi; Lin, Yuxiu; Fang, Ju; Greer, Peter A.; Shi, Hongtao; Ma, Wanli; Su, Yunchao; Yue, Hong

doi:10.1111/cea.12805

Cited by 27 publications

(14 citation statements)

References 49 publications

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“…With regard of the central roles of pro-inflammatory gene transcription for the NF-κB pathway ( 51 ), reductions of TNF-α, IL-1β, IL-6, CCL2, and CXCL-8 release in in vitro coculture by IL-37b may partly rely on the suppressed transcriptional activity of NF-κB. Activation of ERK1/2 and Akt pathways has been reported to involve in lung inflammation and alveolar remodeling ( 52 , 53 ). Consequently, IL-37b-attenuated phosphorylation of ERK1/2 and Akt in eosinophils and BEAS-2B cells, at least in part, can account for the diminished airway thickness in asthmatic mice.…”

Section: Discussionmentioning

confidence: 99%

Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils

Zhu

Dong

et al. 2018

Front. Immunol.

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IL-1 family regulatory cytokine IL-37b can suppress innate immunity and inflammatory activity in inflammatory diseases. In this study, IL-37b showed remarkable in vitro suppression of inflammatory tumor necrosis factor-α, IL-1β, IL-6, CCL2, and CXCL8 production in the coculture of human primary eosinophils and human bronchial epithelial BEAS-2B cells with the stimulation of bacterial toll-like receptor-2 ligand peptidoglycan, while antagonizing the activation of intracellular nuclear factor-κB, PI3K–Akt, extracellular signal-regulated kinase 1/2, and suppressing the gene transcription of allergic inflammation-related PYCARD, S100A9, and CAMP as demonstrated by flow cytometry, RNA-sequencing, and bioinformatics. Results therefore elucidated the novel anti-inflammation-related molecular mechanisms mediated by IL-37b. Using the house dust mite (HDM)-induced humanized asthmatic NOD/SCID mice for preclinical study, intravenous administration of IL-37b restored the normal plasma levels of eosinophil activators CCL11 and IL-5, suppressed the elevated concentrations of Th2 and asthma-related cytokines IL-4, IL-6, and IL-13 and inflammatory IL-17, CCL5, and CCL11 in lung homogenate of asthmatic mice. Histopathological results of lung tissue illustrated that IL-37b could mitigate the enhanced mucus, eosinophil infiltration, thickened airway wall, and goblet cells. Together with similar findings using the ovalbumin- and HDM-induced allergic asthmatic mice further validated the therapeutic potential of IL-37b in allergic asthma. The above results illustrate the novel IL-37-mediated regulation of intracellular inflammation mechanism linking bacterial infection and the activation of human eosinophils and confirm the in vivo anti-inflammatory activity of IL-37b on human allergic asthma.

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Section: Discussionmentioning

confidence: 99%

Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils

Zhu

Dong

et al. 2018

Front. Immunol.

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“…Inhibition of mTOR signaling has immunosuppressive effects on T cells, antigen-presenting cells, B cells, and NKT cells that participate in the pathogenesis of asthma [ 13 – 15 ]. mTORC1 inhibition by rapamycin has been shown to attenuate Th2 and Th17 inflammation in asthma models [ 16 , 17 ], whereas the mTORC2/Akt pathway plays an important role in modulating airway smooth muscle remodeling in asthma [ 18 ]. AS-IV has been suggested to exert cardiac protection through inhibition of mTORC1 signaling [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV Ameliorates Airway Inflammation in an Established Murine Model of Asthma by Inhibiting the mTORC1 Signaling Pathway

Jin

Wang

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Astragaloside IV (AS-IV), a main active constituent of Astragalus membranaceus, has been confirmed to have antiasthmatic effects. However, it remained unclear whether the beneficial effects of AS-IV on asthma were attributed to the mTOR inhibition; this issue was the focus of the present work. BALB/c mice were sensitized and challenged with ovalbumin followed with 3 weeks of rest/recovery and then reexposure to ovalbumin. AS-IV was administrated during the time of rest and reexposure. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokines (IL-4, IL-5, IL-13, IL-17, and INF-γ), and CD4+CD25+Foxp3+Treg cells in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling were examined. AS-IV markedly suppressed airway hyperresponsiveness and reduced IL-4, IL-5, and IL-17 levels and increased INF-γ levels in the BALF. Histological studies showed that AS-IV markedly decreased inflammatory infiltration in the lung tissues. Notably, AS-IV inhibited mTORC1 activity, whereas it had limited effects on mTORC2, as assessed by phosphorylation of mTORC1 and mTORC2 substrates S6 ribosomal protein, p70 S6 Kinase, and Akt, respectively. CD4+CD25+Foxp3+Treg cells in BALF were not significantly changed by AS-IV. Together, these results suggest that the antiasthmatic effects of AS-IV were at least partially from inhibiting the mTORC1 signaling pathway.

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“…Other previous studies have also confirmed the increase of ASMC mass following exposure to inflammatory factors (8), implying the complex interplay among inflammation, ASMCs and asthma attacks. Therefore, attenuating hypertrophy and hyperplasia of ASMCs has been proposed to be a promising method for inhibiting airway remodeling and managing asthma (1,9).…”

Section: Introductionmentioning

confidence: 99%

Rhynchophylline attenuates allergic bronchial asthma by inhibiting transforming growth factor‑β1‑mediated Smad and mitogen‑activated protein kinase signaling transductions in�vivo and in�vitro

Wang¹,

Li²,

Zhao

et al. 2018

Exp Ther Med

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Rhynchophylline (Rhy) is a major active component of Uncaria rhynchophylla and exhibits the potential to inhibit the proliferation of airway smooth muscle cells (ASMCs). In the current study, it was hypothesized that Rhy serves a key role in the anti-asthma effect of Uncaria rhynchophylla by inhibiting transforming growth factor-β1 (TGF-β1)-mediated activation of Smad and mitogen-activated protein kinase (MAPK) signaling. Allergic asthma was induced in mice using ovalbumin (OVA), and the effect of Rhy treatment on inflammatory and allergic responses in the bronchoalveolar lavage fluid (BALF) and serum of mice was determined. Subsequently, the changes in TGF-β1-induced Smad and MAPK signaling following Rhy administration were detected to determine the mechanism associated with this treatment. In addition, TGF-β1 was employed to induce hyperplasia of ASMCs, and the effect of Rhy on proliferation of ASMCs, and Smad and MAPK signaling in vitro was also assessed. The administration of Rhy attenuated the recruitment of eosinophils in BALF induced by OVA, which was associated with the suppressed production of immunoglobulin E, interleukin (IL)-13, IL-4 and IL-5. At the molecular level, the administration of Rhy suppressed the expression levels of TGF-β1, Smad4, p-Smad2 and p-Smad3, while it induced the expression of Smad7, indicating the inhibitory effect of Rhy on TGF-β1-mediated Smad and MAPK signaling. Furthermore, Rhy inhibited the proliferation of ASMCs and, similar to the results of the in vivo assay, it blocked the pro-hyperplasia signaling transduction in vitro. In conclusion, the current study demonstrated the anti-asthma effect of Rhy, which depended on the inhibition of TGF-β1-mediated Smad and MAPK signaling.

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Calpain‐activated mTORC2/Akt pathway mediates airway smooth muscle remodelling in asthma

Abstract: Our results indicate that calpain mediates cytokine-induced collagen-I synthesis and proliferation of ASMCs via the mTORC2/Akt signalling pathway, thereby regulating airway smooth muscle remodelling in asthma.

Cited by 27 publications

References 49 publications

Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils

Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils

Astragaloside IV Ameliorates Airway Inflammation in an Established Murine Model of Asthma by Inhibiting the mTORC1 Signaling Pathway

Rhynchophylline attenuates allergic bronchial asthma by inhibiting transforming growth factor‑β1‑mediated Smad and mitogen‑activated protein kinase signaling transductions in�vivo and in�vitro

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