IFNβ对致病性肺TNFR2 cDC2s进行体内重编程可抑制屋尘螨诱导的哮喘。
In vivo reprogramming of pathogenic lung TNFR2 cDC2s by IFNβ inhibits HDM-induced asthma.
作者信息
Mansouri Samira, Gogoi Himanshu, Pipkin Mauricio, Machuca Tiago N, Emtiazjoo Amir M, Sharma Ashish K, Jin Lei
机构信息
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Florida, Gainesville, FL 32610, USA.
出版信息
Sci Immunol. 2021 Jul 9;6(61). doi: 10.1126/sciimmunol.abi8472.
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 (T) maintaining lung tolerance at steady state but promotes T2 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 T2-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 T 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.
哮喘是一种常见的炎症性肺部疾病，目前尚无治愈方法。此前，我们发现了一种肺TNFR2传统DC2亚群（cDC2s），它能诱导调节性T细胞（T细胞）在稳态下维持肺耐受性，但在屋尘螨（HDM）诱导的哮喘过程中促进T2反应。肺IFNβ对于TNFR2 cDC2s介导的肺耐受性至关重要。在此，我们表明外源性IFNβ将促进T2的致病性TNFR2 cDC2s重新编程为耐受性DC，减轻嗜酸性哮喘并预防哮喘加重。机制上，吸入的IFNβ而非IFNα激活了致病性肺TNFR2 cDC2s中的ERK2信号，导致脂肪酸氧化（FAO）增强和肺T细胞诱导。最后，人IFNβ在体外将来自肺气肿患者的致病性人肺TNFR2 cDC2s重新编程。因此，我们确定了一条IFNβ特异性的ERK2-FAO途径，可用于DC治疗。
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