Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by exaggerated airway inflammatory responses and heightened susceptibility to influenza virus. The mechanisms of which are unknown.
In this study we infected primary bronchial epithelial cells (pBECs) from COPD and healthy subjects with human influenza H3N2 or H1N1.
Infection led to significantly higher activation of NF-κB and inflammatory cytokines production (IL-6/-8/-1β), but resulted in impaired induction of antiviral type I interferon (IFN)-β/-l in COPD, leading to higher viral replication. A20, an important negative regulator of NF-κB, was not induced by infection in COPD. Ectopic expression of A20 decreased NF-κB phosphorylation but minimally affected IFN-β induction.
This reduced level of A20 was the result of increased induction of miR-125a/b. miR-125a/b antagomiRs increased A20 expression and decreased NF-κB phosphorylation, but IFN-β was also markedly increased. TargetScan analysis also showed the antiviral adaptor protein MAVS is a potential target of miR-125a/b. MAVS protein expression was reduced in COPD. By using MAVS-3′UTR-luciferase reporter constructs and miR-125a/b mimetics and immunoprecipitation, enhanced miR-125a/b targeted the putative binding region on 3′UTR, leading to reduced MAVS expression and IFN-β induction in COPD.
In conclusion, influenza virus infection led to enhanced inflammatory but reduced antiviral responses in COPD. miR-125a/b targets A20 and MAVS, leading to enhanced NF-κB activation and impaired IFN response in COPD. miR-125a/b antagomiRs suppressed NF-kB activation and increased IFN-β induction via increased A20 and MAVS, respectively.
- Copyright ©the authors 2016
