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
View: Text | PDF
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

×

Figure 4

IAV infection increases the levels of miR-125 and -b that suppress the production of A20, increase inflammatory responses, and reduce antiviral responses in human COPD pBECs and experimental COPD.

Options: View larger image (or click on image) Download as PowerPoint
IAV infection increases the levels of miR-125 and -b that suppress the p...
pBECs were infected with human IAV H3N2 or H1N1, and (A) miR-125a and -b levels were assessed at 24 hours. Data are mean ± SEM, n = 15 per group. *P ≤ 0.05 versus uninfected media control, +P ≤ 0.05 versus healthy or smoker control. (B) pBECs were treated with miR-125a or -b antagomir and were infected, and the levels of A20, phospho-p65, IFN-β, and IFN-λ1 were assessed. Densitometry results (Supplemental Figure 3B, representative immunoblot) were calculated as A20 or phospho-p65/GAPDH ratios and expressed as fold change from untreated, uninfected 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 group. (C) BALB/c mice were exposed to cigarette smoke (Smk) or normal air (Air) for 8 weeks, inoculated with IAV H1N1 (A/PR/8/34, 8 pfu) or media (Sham) on the last day of smoke exposure, and sacrificed 7 days postinfection (dpi). The levels of miR-125a and -b were measured. Data are mean ± SEM, n = 6–8 per group. *P ≤ 0.05 versus Sham group, +P ≤ 0.05 versus Air-infected or uninfected group. (D) In other groups, on the last day of smoke exposure, mice were treated with miR-125a or -b antagomir alone or in combination and infected with IAV, and (E) airway histological scores were assessed. Data are mean ± SEM, n = 6–8 per group. *P ≤ 0.05 versus infected and scrambled treated Air controls, +P ≤ 0.05 versus infected and scramble-treated Smk group. (F) The protein levels of A20, phospho-p65, and IFN-β in lung homogenates were also measured. Densitometry results (Supplemental Figure 4D) were calculated as A20 or phospho-p65/β-actin ratios and expressed as fold change from untreated, uninfected control. Data are mean ± SEM, n = 6–8 per group. *P ≤ 0.05 versus infected scrambled-treated Air group, +P ≤ 0.05 versus infected scrambled Smk group. Statistical differences were determined with one-way ANOVA followed by Bonferroni post-test.