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In vivo reprogramming of pathogenic lung TNFR2+ cDC2s by IFNβ inhibits HDM-induced asthma.

ABSTRACT: 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.

SUBMITTER: Mansouri S

PROVIDER: S-EPMC8323989 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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In vivo reprogramming of pathogenic lung TNFR2+ cDC2s by IFNβ inhibits HDM-induced asthma.

Mansouri Samira S Gogoi Himanshu H Pipkin Mauricio M Machuca Tiago N TN Emtiazjoo Amir M AM Sharma Ashish K AK Jin Lei L

Science immunology 20210701 61

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+</sup ...[more]

PMID: 34244314

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