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

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Tresa George, Matthew Bell, Mainak Chakraborty, David P. Siderovski, Mark A. Giembycz, Robert Newton, Alexander Larcombe.


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 inflammation, three weeks of intranasal HDM (25 μg, 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.

Partial Text

Asthma is typically an allergic inflammatory disease of the airways characterized by chronic inflammation, pulmonary eosinophilia, airways hyperreactivity (AHR) and mucus hypersecretion [1]. While allergens, such as house dust mite (HDM), are major triggers for allergic asthma [2], inhaled glucocorticoids, or corticosteroids (ICS), reduce airways inflammation and are the most effective drugs in the treatment of mild to moderate asthma [3]. However, in more severe disease, as well as in disease exacerbations, neutrophilic inflammation is common and ICSs show lower clinical efficacy [1, 3]. Treatment guidelines therefore recommend the use of inhaled long-acting β2-adrenoceptor agonist/ICS combination therapy, which produce greater clinical benefit compared to increasing the dose of ICS [3].

The consequences of RGS2 deficiency in a murine model of airways inflammation induced by 3 weeks of i.n. HDM exposure are described and the data are summarized as S2 Table. As previously reported [27], HDM inhalation reduced lung function, evidenced by increased airways resistance and reduced compliance, and elicited a mixed granulocytic inflammation with attendant mucus hypersecretion. In terms of lung function, compared to wild-type, the Rgs2-/- animals demonstrated AHR in both the PBS- and the HDM-exposure groups following challenge with methacholine, an agonist that acts at Gαq-coupled muscarinic M3 receptors to mediate ASM contraction [36, 37]. This involved not only absolute reductions in lung function, but also an enhanced, or exaggerated, propensity to lose lung function in the Rgs2-/- animals. Thus, RGS2 is protective against a contractile agonist both in control and inflamed lungs. Similarly, baseline resistance was modestly elevated in the HDM-exposed group compared to PBS control. Given that RGS2 expression is present, indeed unaltered in the HDM-exposed animals, these data demonstrate a tonic protective role for RGS2 in HDM-induced inflammation. Furthermore, lack of change in RGS2 expression following HDM exposure means that other mechanisms must explain the observed HDM-induced deterioration in lung function. Since inflammation induced by HDM exposure will stimulate pro-inflammatory and contractile mediator release, as well as receptor expression [2], it is likely that such events are responsible for the increase in baseline resistance in the absence of the protective effects of RGS2. Similarly, RGS2 deficiency increased airways stiffness, i.e. reduced compliance, and this occurred in both the PBS control and the HDM-treated animals, both at baseline and following methacholine challenge. Such data are consistent with the known effects of RGS2 loss in the vasculature [24, 38]. Furthermore, these data add to previous reports that RGS2 is bronchoprotective in normal healthy lungs and in an ovalbumin model of lung inflammation [13, 14]. Equally, the recent finding that RGS2 mRNA expression is induced in the human airways 6 h following budesonide inhalation supports the concept that enhanced RGS2 expression, due to ICS alone, or possibly due to the synergy produced by an ICS/LABA combination therapy, may contribute towards the improved lung function produced by these therapeutic interventions [9, 13, 17].




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