Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease

• Published in: Frontiers in immunology Vol. 12; p. 737245
• Main Authors: Yánez, Diana C, Papaioannou, Eleftheria, Chawda, Mira M, Rowell, Jasmine, Ross, Susan, Lau, Ching-In, Crompton, Tessa
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 10.09.2021
• Subjects: airway inflammation; Animals; Anti-Asthmatic Agents - administration & dosage; Anti-Inflammatory Agents - administration & dosage; Asthma - drug therapy; Asthma - immunology; Asthma - metabolism; Benzimidazoles - administration & dosage; CD4 T-cell; Chemotaxis, Leukocyte - drug effects; Cytokines - metabolism; Disease Models, Animal; Female; Immunology; Injections, Intraperitoneal; Lung - drug effects; Lung - immunology; Lung - metabolism; Male; Mice; Mice, Inbred C57BL; Phenylurea Compounds - administration & dosage; Pneumonia - drug therapy; Pneumonia - immunology; Pneumonia - metabolism; Signal Transduction; smoothened (SMO); Smoothened Receptor - antagonists & inhibitors; Smoothened Receptor - genetics; Smoothened Receptor - metabolism; Sonic Hedgehog (Shh); Th2; Th2 Cells - drug effects; Th2 Cells - immunology; Th2 Cells - metabolism; airway inflammation; CD4 T-cell; smoothened (SMO); Sonic Hedgehog (Shh); Th2
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.737245

Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of , , , and the mucin gene in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway.