Abstract
Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-γ (IFN-γ) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal transducer and activator of transcription 1 (STAT1) activation by IFN-γ is a key signaling pathway in Th1 inflammation; however, its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In this study, we challenged wild-type (WT) and Stat1-/- mice with mixed allergens (MA) augmented with c-di-GMP [bis-(3'-5')-cyclic dimeric guanosine monophosphate], an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared with WT mice, Stat1-/- had reduced neutrophils, Th1, and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroids significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1-/- mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1-/- mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.
Highlights
Corticosteroids have broad anti-inflammatory effects that contribute to the effective management of asthma symptoms and exacerbations
Our studies demonstrate that corticosteroid insensitivity remains in the absence of STAT1 signaling during severe allergic airway inflammation
Wild type (WT) and Stat1-/- mice challenged with c-di-GMP + mixed allergen (MA) exhibited increased total Bronchoalveolar lavage fluid (BAL) immune cells compared to PBS-challenged wild type (WT) mice (Figure 1B)
Summary
Corticosteroids have broad anti-inflammatory effects that contribute to the effective management of asthma symptoms and exacerbations. Wild type (WT) and Stat1-/- mice challenged with c-di-GMP + MA exhibited increased total BAL immune cells compared to PBS-challenged WT mice (Figure 1B). Differential immune cell analyses show that c-di-GMP + MA-challenged WT mice exhibited significantly increased eosinophil, neutrophil, macrophage, and lymphocyte numbers in BAL (Figure 1D).
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