In vivo reprogramming of pathogenic lung TNFR2+ cDC2s by IFNβ inhibits HDM-induced asthma.
Samira MansouriHimanshu GogoiMauricio PipkinTiago N MachucaAmir M EmtiazjooAshish K SharmaLei JinPublished in: Science immunology (2022)
Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2+ conventional DC2 subset (cDC2s) that induces regulatory T cells (Tregs) maintaining lung tolerance at steady state but promotes TH2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2+ cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed TH2-promoting pathogenic TNFR2+ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2+ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung Treg induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2+ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy.
Keyphrases
- dendritic cells
- chronic obstructive pulmonary disease
- regulatory t cells
- immune response
- lung function
- cell cycle
- allergic rhinitis
- fatty acid
- cell proliferation
- signaling pathway
- oxidative stress
- cystic fibrosis
- endothelial cells
- air pollution
- risk assessment
- climate change
- hydrogen peroxide
- smoking cessation
- acute respiratory distress syndrome
- mesenchymal stem cells
- mechanical ventilation
- drug induced
- health risk assessment
- electron transfer
- replacement therapy