scholarly journals Glutamine deficiency shifts the asthmatic state toward neutrophilic airway inflammation

2021 ◽  
Author(s):  
June-Mo Kim ◽  
Yoo-Na Im ◽  
Yun-Jo Chung ◽  
Jung-ho Youm ◽  
Suhn-Young Im ◽  
...  
Keyword(s):  
Glutamine Synthetase ◽  
Airway Inflammation ◽  
P38 Mapk ◽  
Allergic Airway Inflammation ◽  
Neutrophil Infiltration ◽  
Leukotriene B4 ◽  
Negative Regulator ◽  
Asthma Model ◽  
Mitogen Activated Protein ◽  
Si Rna

Background: The administration of L-glutamine (Gln) suppresses allergic airway inflammation via the rapid upregulation of MAPK phosphatase (MKP)-1, which functions as a negative regulator of inflammation by deactivating p38 and JNK mitogen-activated protein kinases (MAPKs). However, the role of endogenous Gln remains to be elucidated. Therefore, we investigated the mechanism by which endogenous Gln regulates MKP-1 induction and allergic airway inflammation in an ovalbumin-based murine asthma model. Methods: We depleted endogenous Gln levels using l-γ-glutamyl- p-nitroanilide (GPNA), an inhibitor of the Gln transporter ASCT2, and glutamine synthetase small interfering (si)RNA. Lentivirus expressing MKP-1 was injected to achieve overexpression of MKP-1. Asthmatic phenotypes were assessed using our previously developed ovalbumin-based murine model, which is suitable for examining sequential asthmatic events, including neutrophil infiltration. Gln levels were analyzed using a Gln assay kit. Results: GPNA or glutamine synthetase siRNA successfully depleted endogenous Gln levels. Importantly, homeostatic MKP-1 induction did not occur at all, which resulted in prolonged p38 MAPK and cytosolic phospholipase A (cPLA ) phosphorylation in Gln-deficient mice. Gln deficiency augmented all examined asthmatic reactions, but it exhibited a strong bias toward increasing the neutrophil count, which was not observed in MKP-1-overexpressing lungs. This neutrophilia was inhibited by a cPLA inhibitor and a leukotriene B4 inhibitor, but not by dexamethasone. Conclusion: Gln deficiency leads to the impairment of MKP-1 induction and activation of p38 MAPK and cPLA , resulting in the augmentation of neutrophilic, more so than eosinophilic, airway inflammation.

scholarly journals MicroRNA-21 Promotes Allergic Airway Inflammation and AHR and Inhibits Mesenchymal Stem Cell Migration in Cockroach Allergen Induced Asthma Model

2021 ◽  
Author(s):  
Tianli Cheng ◽  
jianfu heng ◽  
Quanhui Mei ◽  
Lijun Chen ◽  
Feng Zeng
Keyword(s):  
Mouse Model ◽  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Airway Hyperreactivity ◽  
Negative Regulator ◽  
Mouse Bone Marrow ◽  
Asthma Model ◽  
Gene Assay

Abstract BackgroundMesenchymal stem cells (MSCs) have been used to treat asthma in a mouse model. However, the efficacy and mechanism of MSCs are not elucidated. MicroRNAs (miRNAs) play a key rolein asthma and related to the aim of this study was to illustrate the role of miR21 and its influence on MSC migration in asthma model. MethodsA mouse model of asthma was established using cockroach extract (CRE), and miR-21 expression was examined. A miR-21 lentivirus construct was used to investigate the role of miR-21 in vivo and in vitro in mouse bone marrow-derived (BM-) MSCs. A TOPFlash reporter gene assay was used to study the signaling downstream of miR-21. IL-4, IL-5, IL-13, IgE, and IgG1 levels in bronchoalveolar lavage fluids were determined by enzyme-linked immunosorbent assays.ResultsMiR-21 was upregulated in CRE-induced asthmatic mice. MiR-21 promoted allergic airway inflammation and airway hyperreactivity by inhibiting BM-MSC migration. β-Catenin was found to act downstream of miR-21 as a negative regulator of miR-21. Rescue experiments verified that miR-21 inhibited BM-MSC migration by suppressing Wnt/β-catenin signaling.ConclusionMiR-21 promotes allergic airway inflammation and AHR and inhibits BM-MSC migration through Wnt/β-catenin signaling, which may serve as an effective therapeutic target for asthma.

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

2016 ◽  
Vol 306 ◽  
pp. 17-26 ◽  
Author(s):  
Vaibhav Shrirang Dhawale ◽  
Venkateswara Rao Amara ◽  
Pinakin Arun Karpe ◽  
Vajir Malek ◽  
Deep Patel ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Asthma Model

scholarly journals Role of Leukotriene B4 Receptor-2 in Mast Cells in Allergic Airway Inflammation

2019 ◽  
Vol 20 (12) ◽  
pp. 2897 ◽  
Author(s):  
Sun-Young Kwon ◽  
Jae-Hong Kim
Keyword(s):  
Mast Cells ◽  
Airway Inflammation ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Leukotriene B4 ◽  
Vascular Endothelial ◽  
Effector Cells ◽  
Elevated Expression ◽  
Leukotriene B4 Receptor ◽  
Endothelial Growth Factor

Mast cells are effector cells in the immune system that play an important role in the allergic airway inflammation. Recently, it was reported that BLT2, a low-affinity leukotriene (LT) B4 receptor, plays a pivotal role in the pathogenesis of allergic airway inflammation through its action in mast cells. We observed that highly elevated expression levels of BLT2 are critical for the pathogenesis leading to allergic airway inflammation, and that if BLT2 expression is downregulated by siBLT2-mediated knockdown, allergic inflammation is dramatically alleviated. Furthermore, we demonstrated that BLT2 mediates the synthesis of vascular endothelial growth factor (VEGF) and Th2 cytokines, such as interleukin (IL)-13, in mast cells during allergic inflammation. Based on the critical roles of BLT2 in mast cells in allergic inflammation, anti-BLT2 strategies could contribute to the development of new therapies for allergic airway inflammation.

scholarly journals A20-binding inhibitor of NF-κB (ABIN) 2 negatively regulates allergic airway inflammation

2018 ◽  
Vol 215 (11) ◽  
pp. 2737-2747 ◽  
Author(s):  
Sonia Ventura ◽  
Florencia Cano ◽  
Yashaswini Kannan ◽  
Felix Breyer ◽  
Michael J. Pattison ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Drug Target ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Negative Regulator ◽  
Disease Models ◽  
Wild Type ◽  
Dust Mite ◽  
Airway Responses ◽  
Deficient Mice

TPL-2 MAP 3-kinase promotes inflammation in numerous mouse disease models and is an attractive anti-inflammatory drug target. However, TPL-2–deficient (Map3k8−/−) mice develop exacerbated allergic airway inflammation to house dust mite (HDM) compared with wild type controls. Here, we show that Map3k8D270A/D270A mice expressing kinase dead TPL-2 had an unaltered response to HDM, indicating that the severe airway inflammation observed in Map3k8−/− mice is not due to blockade of TPL-2 signaling and rather reflects a TPL-2 adaptor function. Severe allergic inflammation in TPL-2–deficient mice was likely due to reduced levels of ABIN-2 (TNIP2), whose stability depends on TPL-2 expression. Tnip2E256K knock-in mutation, which reduced ABIN-2 binding to A20, augmented the HDM-induced airway inflammation, but did not affect TPL-2 expression or signaling. These results identify ABIN-2 as a novel negative regulator of allergic airway responses and importantly indicate that TPL-2 inhibitors would not have unwanted allergic comorbidities.

scholarly journals Schizophyllum commune induces IL-17-mediated neutrophilic airway inflammation in OVA-induced asthma model mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jun Hanashiro ◽  
Yasunori Muraosa ◽  
Takahito Toyotome ◽  
Koichi Hirose ◽  
Akira Watanabe ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Asthma Exacerbation ◽  
Schizophyllum Commune ◽  
Allergic Airway Inflammation ◽  
Asthma Severity ◽  
Outdoor Air ◽  
Intratracheal Administration ◽  
Basidiomycetous Fungus ◽  
Asthma Model ◽  
Indoor And Outdoor

AbstractSchizophyllum commune is a ubiquitous basidiomycetous fungus typically found across the world, which has been detected in indoor and outdoor air. Some studies indicated that sensitization to S. commune is correlated with asthma severity in patients. Patients with chronic severe or acute fatal asthma have neutrophil-dominant airway inflammation. We hypothesized that S. commune can exacerbate asthma. To test this hypothesis, we evaluated the direct immunomodulatory activities of S. commune in allergic airway inflammation induced by non-fungal sensitization. Ovalbumin (OVA)-induced asthma model mice were generated using wild-type (WT) and Il-17a−/−Il-17f−/− mice that were intratracheally exposed to S. commune, then immune responses in the lungs were assessed after 24 h. Intratracheal administration of S. commune in OVA-induced asthma model mice enhanced neutrophilic airway inflammation, increased the mRNA expression of CXCL1 and CXCL2 in the lungs, and provoked IL-17A, and IL-17F production in BAL fluid. In addition, neutrophilic airway inflammation was significantly inhibited in Il-17a−/−Il-17f−/− mice compared with those found in WT mice. We demonstrated that S. commune induces neutrophilic airway inflammation in OVA-induced asthma model mice, and IL-17A and IL-17F had central roles in this activity. As S. commune inhabits the general environment, including indoor and outdoor air, our results suggested that S. commune is a causative agent of asthma exacerbation. This study has provided clues regarding the mechanisms behind fungi and asthma exacerbation.

scholarly journals Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases

2016 ◽  
Vol 36 (18) ◽  
pp. 2403-2417 ◽  
Author(s):  
Sharadha Dayalan Naidu ◽  
Calum Sutherland ◽  
Ying Zhang ◽  
Ana Risco ◽  
Laureano de la Vega ◽  
...  
Keyword(s):  
Heat Shock ◽  
P38 Mapk ◽  
Nuclear Translocation ◽  
Heat Shock Factor ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Heat Shock Factor 1 ◽  
Mitogen Activated Protein ◽  
P38 Mapks

Heat shock factor 1 (HSF1) monitors the structural integrity of the proteome. Phosphorylation at S326 is a hallmark for HSF1 activation, but the identity of the kinase(s) phosphorylating this site has remained elusive. We show here that the dietary agent phenethyl isothiocyanate (PEITC) inhibits heat shock protein 90 (Hsp90), the main negative regulator of HSF1; activates p38 mitogen-activated protein kinase (MAPK); and increases S326 phosphorylation, trimerization, and nuclear translocation of HSF1, and the transcription of a luciferase reporter, as well as the endogenous prototypic HSF1 target Hsp70.In vitro, all members of the p38 MAPK family rapidly and stoichiometrically catalyze the S326 phosphorylation. The use of stable knockdown cell lines and inhibitors indicated that among the p38 MAPKs, p38γ is the principal isoform responsible for the phosphorylation of HSF1 at S326 in cells. A protease-mass spectrometry approach confirmed S326 phosphorylation and unexpectedly revealed that p38 MAPK also catalyzes the phosphorylation of HSF1 at S303/307, previously known repressive posttranslational modifications. Thus, we have identified p38 MAPKs as highly efficient catalysts for the phosphorylation of HSF1. Furthermore, our findings suggest that the magnitude and persistence of activation of p38 MAPK are important determinants of the extent and duration of the heat shock response.

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