Journal Article

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

Whitehead, Gregory S., Moran, Timothy P., Nakano, Hideki, Thomas, Seddon Y., Ward, James M., Flake, Gordon P., Cook, Donald N., Nakano, Keiko, Shalaby, Karim H.

2017

Overview

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

• Publisher: American Society for Clinical Investigation
• Subject: Adjuvants / Airway management / Allergens / Allergies / Animals / Antigens / Asthma / Asthma - metabolism / Asthma - physiopathology / Biomedical research / Bronchial Hyperreactivity - physiopathology / Cell Differentiation / Cytokines / Cytokines - metabolism / Dendritic cells / Disease Models, Animal / Eosinophils - cytology / Epithelial cells / Gene expression / Genetic aspects / Health aspects / Helper cells / House dust / Hypersensitivity - metabolism / Hypersensitivity - physiopathology / Inflammation / Inflammation - physiopathology / Interleukin-17 - metabolism / Leukocytes (eosinophilic) / Leukocytes (neutrophilic) / Ligands / Lung - physiopathology / Lymph nodes / Lymphocytes T / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular modelling / Neutrophils - cytology / Ovalbumin - metabolism / Proteinase / Proteins / Recruitment / Respiratory function / Respiratory Hypersensitivity - metabolism / Respiratory Hypersensitivity - physiopathology / Respiratory tract diseases / Signal Transduction / Th17 Cells - cytology / Th2 Cells - cytology / TNF inhibitors / Toll-like receptors / Toll-Like Receptors - metabolism / Tumor necrosis factor / Tumor Necrosis Factor-alpha - physiology / Tumor necrosis factor-TNF