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Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19 #MMPMID33159154
Liu Y; Lv J; Liu J; Li M; Xie J; Lv Q; Deng W; Zhou N; Zhou Y; Song J; Wang P; Qin C; Tong WM; Huang B
Cell Res 2020[Dec]; 30 (12): 1078-1087 PMID33159154show ga
Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-beta or IFN-gamma upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.