A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation

Abstract

BackgroundAsthma exacerbations are associated with the recruitment of neutrophils to the lungs. These cells release proteases and mediators, many of which act at G protein-coupled receptors (GPCRs) that couple via Gq to promote bronchoconstriction and inflammation. Common asthma therapeutics up-regulate expression of the regulator of G protein signalling (RGS), RGS2. As RGS2 reduces signaling from Gq-coupled GPCRs, we have defined role(s) for this GTPase-activating protein in an acute neutrophilic model of lung inflammation.MethodsWild type and Rgs2−/− C57Bl6 mice were exposed to nebulized lipopolysaccharide (LPS). Lung function (respiratory system resistance and compliance) was measured using a SCIREQ flexivent small animal ventilator. Lung inflammation was assessed by histochemistry, cell counting and by cytokine and chemokine expression in bronchoalveolar lavage (BAL) fluid.ResultsLipopolysaccharide inhalation induced transient airways hyperreactivity (AHR) and neutrophilic lung inflammation. While AHR and inflammation was greatest 3 h post-LPS exposure, BAL neutrophils persisted for 24 h. At 3 h post-LPS inhalation, multiple inflammatory cytokines (CSF2, CSF3, IL6, TNF) and chemokines (CCL3, CCL4, CXCL1, CXCL2) were highly expressed in the BAL fluid, prior to declining by 24 h. Compared to wild type counterparts, Rgs2−/− mice developed significantly greater airflow resistance in response to inhaled methacholine (MCh) at 3 h post-LPS exposure. At 24 h post-LPS exposure, when lung function was recovering in the wild type animals, MCh-induced resistance was increased, and compliance decreased, in Rgs2−/− mice. Thus, Rgs2−/− mice show AHR and stiffer lungs 24 h post-LPS exposure. Histological markers of inflammation, total and differential cell counts, and major cytokine and chemokine expression in BAL fluid were similar between wild type and Rgs2−/− mice. However, 3 and 24 h post-LPS exposure, IL12B expression was significantly elevated in BAL fluid from Rgs2−/− mice compared to wild type animals.ConclusionsWhile Rgs2 is bronchoprotective in acute neutrophilic inflammation, no clear anti-inflammatory effect was apparent. Nevertheless, elevated IL12B expression in Rgs2−/− animals raises the possibility that RGS2 could dampen Th1 responses. These findings indicate that up-regulation of RGS2, as occurs in response to inhaled corticosteroids and long-acting β2-adrenoceptor agonists, may be beneficial in acute neutrophilic exacerbations of airway disease, including asthma.Electronic supplementary materialThe online version of this article (10.1186/s13223-018-0266-5) contains supplementary material, which is available to authorized users.

MCTR1 alleviates lipopolysaccharide‐induced acute lung injury by protecting lung endothelial glycocalyx

“…Pulmonary dysfunction begins following lung infection in sepsis-induced ALI mainly due to the release of proinflammatory mediators, such as TNF-α, IL-1β, and IL-6, leading to the loss of alveolar-capillary barrier integrity, neutrophil recruitment, and alveolar edema (Prescott & Angus, 2018). In a previous study, George et al reported that baseline resistance and compliance were not different between LPS-and PBS-exposed mice at 3 h, 6 h, and 24 h after LPS exposure (George, Chakraborty, Giembycz, & Newton, 2018). However, 3 h after LPS exposure, Mch (10-300 mg/ml) challenge induced significantly higher increases in lung resistance than PBS exposure alone.…”

Transcriptome-Level Interactions between Budesonide and Formoterol Provide Insight into the Mechanism of Action of Inhaled Corticosteroid/Long-Acting β2-Adrenoceptor Agonist Combination Therapy in Asthma

“…These include the regulator of G-protein signalling, RGS2, which attenuates signal transduction from G-protein coupled receptors (GPCRs) that act via Gq (Heximer, 2004;Kimple et al, 2011). In vivo, including in models of lung inflammation (George et al, 2017;George et al, 2018;Jiang et al, 2015;Xie et al, 2012), RGS2 is bronchoprotective (Holden et al, 2011). Moreover, in HBECs and smooth muscle cells, LABAs synergize with glucocorticoids to enhance and prolong RGS2 expression (Holden et al, 2011;Holden et al, 2014).…”

Unrestrained Gαi2 Signaling Disrupts Neutrophil Trafficking, Aging, and Clearance

“…They also highly express Gnai2 , with a lower amount of Gnai3 (approximately 1/5 the amount as assessed by RNA sequencing) and little or no Gnai1 or Gnao . Loss of Rgs2 in mice increases neutrophil recruitment to inflamed lungs ( 12 , 13 ). Despite its low expression level, loss of Rgs5 in mice also leads to a more robust recruitment of neutrophils to inflamed lungs ( 14 ).…”