Bilirubin represents a negative regulator of ILC2 in allergic airway inflammation

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.

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Neuropilin-2 is a negative regulator of allergic airway inflammation

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2017.12.572 ◽

2018 ◽

Vol 141 (2) ◽

pp. AB180

Author(s):

Timothy P. Moran ◽

Robert M. Immormino ◽

Hideki Nakano ◽

Michelle L. Hernandez ◽

David B. Peden ◽

...

Keyword(s):

Airway Inflammation ◽

Allergic Airway Inflammation ◽

Negative Regulator

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

10.21203/rs.3.rs-148622/v1 ◽

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.

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Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms

Science Signaling ◽

10.1126/scisignal.aax3332 ◽

2019 ◽

Vol 12 (597) ◽

pp. eaax3332 ◽

Cited By ~ 6

Author(s):

Brenal K. Singh ◽

Wen Lu ◽

Amanda M. Schmidt Paustian ◽

Moyar Q. Ge ◽

Cynthia J. Koziol-White ◽

...

Keyword(s):

Airway Inflammation ◽

Allergic Asthma ◽

Airway Hyperresponsiveness ◽

Allergic Airway Inflammation ◽

Airway Disease ◽

Negative Regulator ◽

Airway Smooth Muscle Cells ◽

T Helper 2

Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (TH2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks TH2 differentiation. Here, we report that targeting diacylglycerol (DAG) kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protected against allergic asthma by simultaneously reducing airway inflammation and AHR though independent mechanisms. Targeted deletion of DGKζ in T cells decreased type 2 inflammation without reducing AHR. In contrast, loss of DGKζ in airway smooth muscle cells decreased AHR but not airway inflammation. T cell–specific enhancement of ERK signaling was only sufficient to limit type 2 airway inflammation, not AHR. Pharmacological inhibition of DGK diminished both airway inflammation and AHR in mice and also reduced bronchoconstriction of human airway samples in vitro. These data suggest that DGK is a previously unrecognized therapeutic target for asthma and reveal that the inflammatory and AHR components of asthma are not as interdependent as generally believed.

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Glutamine deficiency shifts the asthmatic state toward neutrophilic airway inflammation

10.22541/au.162690137.72052318/v1 ◽

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.

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