Corticosteroid Insensitivity Persists in the Absence of STAT1 Signaling in Severe Allergic Airway Inflammation

Brandon W. Lewis, Devine Jackson, Stephanie A. Amici, Joshua Walum, Manel Guessas, Sonia Guessas, Elise Coneglio, Akhila Boda, Mireia Guerau-De-Arellano, Mitchell H. Grayson, Rodney Rodney D. Britt

Research output: Contribution to journalArticlepeer-review


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-gamma (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 the present study, we challenged wild type (WT) and Stat1-/- mice with mixed allergens (MA) augmented with c-di-GMP, an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared to 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). Corticosteroid 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number6
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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