Browsing by Author "Chakraborty, Mainak"

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    A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation
    (2018-10-01) George, Tresa; Chakraborty, Mainak; Giembycz, Mark A; Newton, Robert
    Abstract Background Asthma 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. Methods Wild 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. Results Lipopolysaccharide 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. Conclusions While 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.
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    Expanding Allergen-specific Tr-1 CD4+ T cells to treat Allergic Asthma
    (2017) Chakraborty, Mainak; Santamaria, Pere; Mody, Christopher; Newton, Robert; Giembycz, Mark
    Asthma is a chronic inflammatory disease of the lungs, which is one of the most frequent chronic disease in industrialized nations. The associated morbidity and occasional mortality rates are secondary to an underlying dysfunction of the airway driven by immune-mediated inflammation. Our lab has been developing a nanoparticle based therapy to deliver antigen-specific peptide-major histocompatibility complex to treat autoimmunity, which triggers the induction and expansion of cognate autoregulatory CD4+ Tr1-like cells that suppresses the autoimmune response via secretion of anti-inflammatory cytokines such as IL-10 and TGF-β. We tested this therapeutic avenue in a chronic model of asthma in BALB/c mice, and found that the pMHC-NP therapy triggers allergen-specific Tr-1 cell formation and expansion that can suppress inflammation, promoting the resolution of airways hyper-responsiveness and airway remodeling. Asthma-relevant pMHC class II-coated NPs may therefore represent a viable alternative to current approaches to restore immune homeostasis in allergic individuals.