MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD
Alan C-Y. Hsu, Kamal Dua, Malcolm R. Starkey, Tatt-Jhong Haw, Prema M. Nair, Kristy Nichol, Nathan Zammit, Shane T. Grey, Katherine J. Baines, Paul S. Foster, Philip M. Hansbro, Peter A. Wark
Alan C-Y. Hsu, Kamal Dua, Malcolm R. Starkey, Tatt-Jhong Haw, Prema M. Nair, Kristy Nichol, Nathan Zammit, Shane T. Grey, Katherine J. Baines, Paul S. Foster, Philip M. Hansbro, Peter A. Wark
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Research Article Immunology Pulmonology

MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD

Abstract

Influenza A virus (IAV) infections lead to severe inflammation in the airways. Patients with chronic obstructive pulmonary disease (COPD) characteristically have exaggerated airway inflammation and are more susceptible to infections with severe symptoms and increased mortality. The mechanisms that control inflammation during IAV infection and the mechanisms of immune dysregulation in COPD are unclear. We found that IAV infections lead to increased inflammatory and antiviral responses in primary bronchial epithelial cells (pBECs) from healthy nonsmoking and smoking subjects. In pBECs from COPD patients, infections resulted in exaggerated inflammatory but deficient antiviral responses. A20 is an important negative regulator of NF-κB–mediated inflammatory but not antiviral responses, and A20 expression was reduced in COPD. IAV infection increased the expression of miR-125a or -b, which directly reduced the expression of A20 and mitochondrial antiviral signaling (MAVS), and caused exaggerated inflammation and impaired antiviral responses. These events were replicated in vivo in a mouse model of experimental COPD. Thus, miR-125a or -b and A20 may be targeted therapeutically to inhibit excessive inflammatory responses and enhance antiviral immunity in IAV infections and in COPD.

Authors

Alan C-Y. Hsu, Kamal Dua, Malcolm R. Starkey, Tatt-Jhong Haw, Prema M. Nair, Kristy Nichol, Nathan Zammit, Shane T. Grey, Katherine J. Baines, Paul S. Foster, Philip M. Hansbro, Peter A. Wark

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Figure 3

A20 expression is reduced and negatively regulates inflammatory but not antiviral responses in pBECs from patients with COPD.

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A20 expression is reduced and negatively regulates inflammatory but not ...
(A) pBECs were infected with human IAV H3N2 or H1N1, and the protein levels of A20 were determined at 6 hours and 24 hours. Densitometry results (from Supplemental Figure 2A, representative immunoblot) were calculated as A20 or phospho-p65/GAPDH ratios and expressed as fold change from healthy media control. Data are mean ± SEM, n = 15 per group. *P ≤ 0.05 versus respective uninfected media control, +P ≤ 0.05 versus healthy control. A20 expression was inhibited with a specific siRNA, pBECs were infected with IAVs, and protein levels of (B) A20; (C) phospho-p65; (D) cytokines/chemokines IL-6, CXCL-8, TNF-α, and IL-1β; and antiviral (E) IFN-β and IFN-λ1 were measured 24 hours later. Densitometric ratios (from Supplemental Figure 2C, representative immunoblot) were expressed as fold change from untreated media control. Data are mean ± SEM, n = 3 per group. *P ≤ 0.05 versus untreated, uninfected media control, +P ≤ 0.05 versus untreated infected or uninfected control. Statistical differences were determined with one-way ANOVA followed by Bonferroni post-test.