Corticosteroid insensitivity persists in the absence of STAT1 signaling in severe allergic airway inflammation

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 321; no. 6; pp. L1194 - L1205
• Main Authors: Lewis, Brandon W, Jackson, Devine, Amici, Stephanie A, Walum, Joshua, Guessas, Manel, Guessas, Sonia, Coneglio, Elise, Boda, Akhila V, Guerau-de-Arellano, Mireia, Grayson, Mitchell H, Britt, Jr, Rodney D
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2021
• Subjects: Adrenal Cortex Hormones - metabolism; Allergens - metabolism; Animals; Asthma - metabolism; Eosinophils - metabolism; Female; Hypersensitivity - metabolism; Inflammation - metabolism; Interferon-gamma - metabolism; Lung - metabolism; Male; Mice; Mice, Inbred C57BL; Neutrophils - metabolism; Respiratory Hypersensitivity - metabolism; STAT1 Transcription Factor - metabolism; T-Lymphocytes, Helper-Inducer - metabolism; corticosteroid insensitivity; asthma; Th1 inflammation; STAT1
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00244.2021

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 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, S 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 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 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.