| Title: |
In vivo reprogramming of pathogenic lung TNFR2+ cDC2s by IFNβ inhibits HDM-induced asthma. |
| Authors: |
Mansouri, Samira, Gogoi, Himanshu, Pipkin, Mauricio, Machuca, Tiago N., Emtiazjoo, Amir M., Sharma, Ashish K., Jin, Lei |
| Source: |
Science Immunology; 2021, Vol. 6 Issue 61, p1-14, 14p |
| Abstract: |
IFNβ is a breath of fresh air: Allergen-induced asthma affects millions of people; thus, treatments to alleviate symptoms are needed. Lung inflammation from allergen-induced asthma, specifically house dust mite (HDM) mouse models, is induced by inflammatory lung TNFR2+ conventional DC2s (cDC2). Here, Mansouri et al. demonstrated that treating mice with intranasal IFNβ, an important factor for maintaining immune tolerance in the lung, alleviated asthma symptoms in HDM mouse models by making TNFR2+ cDC2s more tolerogenic. The IFNβ-induced TNFR2+ cDC2s led to the generation of anti-inflammatory Tregs in an ERK- and fatty acid oxidation–dependent manner. These results could be replicated with human lung TNFR2+ cDC2s. Thus, inhaled IFNβ may represent a potential therapy to alleviate allergen-induced asthma in people. 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
