In vivo reprogramming of pathogenic lung TNFR2+ cDC2s by IFN╬▓ inhibits HDM-induced asthma
IFN╬▓ 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 IFN╬▓, an important factor for maintaining immune tolerance in the lung, alleviated asthma symptoms in HDM mouse models by making TNFR2+ cDC2s more tolerogenic. The IFN╬▓-induced TNFR2+ cDC2s led to the generation of anti-inflammatory Tregs in an ERK- and fatty acid oxidationтАУdependent manner. These results could be replicated with human lung TNFR2+ cDC2s. Thus, inhaled IFN╬▓ may represent a potential therapy to alleviate allergen-induced asthma in people.
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)тАУinduced asthma. Lung IFN╬▓ is essential for TNFR2+ cDC2sтАУmediated lung tolerance. Here, we showed that exogenous IFN╬▓ reprogrammed TH2-promoting pathogenic TNFR2+ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFN╬▓, not IFN╬▒, activated ERK2 signaling in pathogenic lung TNFR2+ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung Treg induction. Last, human IFN╬▓ reprogrammed pathogenic human lung TNFR2+ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFN╬▓-specific ERK2-FAO pathway that might be harnessed for DC therapy.
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