title: 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.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Alan C-Y
authors.initials: AC
authors.lastname: Hsu
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Kamal
authors.initials: K
authors.lastname: Dua
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Starkey
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Tatt-Jhong
authors.initials: TJ
authors.lastname: Haw
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Prema M
authors.initials: PM
authors.lastname: Nair
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Kristy
authors.initials: K
authors.lastname: Nichol
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Zammit
authors.affiliation: Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, New South Wales, Australia.|Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wark
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology; D009980:Influenza A virus / Q000502:physiology; D007251:Influenza, Human / Q000150:complications / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology*; D012907:Smoking / Q000009:adverse effects; D014779:Virus Replication
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D011506:Proteins; C426747:TNIP3 protein, human