Dataset Information

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

ABSTRACT: The GTPase-accelerating protein, regulator of G-protein signalling 2 (RGS2) reduces signalling from G-protein-coupled receptors (GPCRs) that signal via G?q. In humans, RGS2 expression is up-regulated by inhaled corticosteroids (ICSs) and long-acting ?2-adrenoceptor agonists (LABAs) such that synergy is produced in combination. This may contribute to the superior clinical efficacy of ICS/LABA therapy in asthma relative to ICS alone. In a murine model of house dust mite (HDM)-induced airways inflammation, three weeks of intranasal HDM (25 ?g, 3×/week) reduced lung function and induced granulocytic airways inflammation. Compared to wild type animals, Rgs2-/- mice showed airways hyperresponsiveness (increased airways resistance and reduced compliance). While HDM increased pulmonary inflammation observed on hematoxylin and eosin-stained sections, there was no difference between wild type and Rgs2-/- animals. HDM-induced mucus hypersecretion was also unaffected by RGS2 deficiency. However, inflammatory cell counts in the bronchoalveolar lavage fluid of Rgs2-/- animals were significantly increased (57%) compared to wild type animals and this correlated with increased granulocyte (neutrophil and eosinophil) numbers. Likewise, cytokine and chemokine (IL4, IL17, IL5, LIF, IL6, CSF3, CXCLl, CXCL10 and CXCL11) release was increased by HDM exposure. Compared to wild type, Rgs2-/- animals showed a trend towards increased expression for many cytokines/chemokines, with CCL3, CCL11, CXCL9 and CXCL10 being significantly enhanced. As RGS2 expression was unaffected by HDM exposure, these data indicate that RGS2 exerts tonic bronchoprotection in HDM-induced airways inflammation. Modest anti-inflammatory and anti-remodelling roles for RGS2 are also suggested. If translatable to humans, therapies that maximize RGS2 expression may prove advantageous.

SUBMITTER: George T

PROVIDER: S-EPMC5249169 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

George Tresa T Bell Matthew M Chakraborty Mainak M Siderovski David P DP Giembycz Mark A MA Newton Robert R

PloS one 20170120 1

The GTPase-accelerating protein, regulator of G-protein signalling 2 (RGS2) reduces signalling from G-protein-coupled receptors (GPCRs) that signal via Gαq. In humans, RGS2 expression is up-regulated by inhaled corticosteroids (ICSs) and long-acting β2-adrenoceptor agonists (LABAs) such that synergy is produced in combination. This may contribute to the superior clinical efficacy of ICS/LABA therapy in asthma relative to ICS alone. In a murine model of house dust mite (HDM)-induced airways infla ...[more]

PMID: 28107494

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Project description:BackgroundNanomaterial inhalation represents a potential hazard for respiratory conditions such as asthma. Cerium dioxide nanoparticles (CeO2NPs) have the ability to modify disease outcome but have not been investigated for their effect on models of asthma and inflammatory lung disease. The aim of this study was to examine the impact of CeO2NPs in a house dust mite (HDM) induced murine model of asthma.ResultsRepeated intranasal instillation of CeO2NPs in the presence of HDM caused the induction of a type II inflammatory response, characterised by increased bronchoalveolar lavage eosinophils, mast cells, total plasma IgE and goblet cell metaplasia. This was accompanied by increases in IL-4, CCL11 and MCPT1 gene expression together with increases in the mucin and inflammatory regulators CLCA1 and SLC26A4. CLCA1 and SLC26A4 were also induced by CeO2NPs + HDM co-exposure in air liquid interface cultures of human primary bronchial epithelial cells. HDM induced airway hyperresponsiveness and airway remodelling in mice were not altered with CeO2NPs co-exposure. Repeated HMD instillations followed by a single exposure to CeO2NPs failed to produce changes in type II inflammatory endpoints but did result in alterations in the neutrophil marker CD177. Treatment of mice with CeO2NPs in the absence of HDM did not have any significant effects. RNA-SEQ was used to explore early effects 24 h after single treatment exposures. Changes in SAA3 expression paralleled increased neutrophil BAL levels, while no changes in eosinophil or lymphocyte levels were observed. HDM resulted in a strong induction of type I interferon and IRF3 dependent gene expression, which was inhibited with CeO2NPs co-exposure. Changes in the expression of genes including CCL20, CXCL10, NLRC5, IRF7 and CLEC10A suggest regulation of dendritic cells, macrophage functionality and IRF3 modulation as key early events in how CeO2NPs may guide pulmonary responses to HDM towards type II inflammation.ConclusionsCeO2NPs were observed to modulate the murine pulmonary response to house dust mite allergen exposure towards a type II inflammatory environment. As this type of response is present within asthmatic endotypes this finding may have implications for how occupational or incidental exposure to CeO2NPs should be considered for those susceptible to disease.

Dataset Information

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

Publications

Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation.

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