Abstract
Fibroblast growth factor 2 (FGF2 or basic FGF) regulates a wide range of cell biological functions including proliferation, angiogenesis, migration, differentiation, and injury repair. However, the roles of FGF2 and the underlying mechanisms of action in influenza A virus (IAV)-induced lung injury remain largely unexplored. In this study, we report that microRNA-194-5p (miR-194) expression is significantly decreased in A549 alveolar epithelial cells (AECs) following infection with IAV/Beijing/501/2009 (BJ501). We found that miR-194 can directly target FGF2, a novel antiviral regulator, to suppress FGF2 expression at the mRNA and protein levels. Overexpression of miR-194 facilitated IAV replication by negatively regulating type I interferon (IFN) production, whereas reintroduction of FGF2 abrogated the miR-194-induced effects on IAV replication. Conversely, inhibition of miR-194 alleviated IAV-induced lung injury by promoting type I IFN antiviral activities in vivo. Importantly, FGF2 activated the retinoic acid-inducible gene I signaling pathway, whereas miR-194 suppressed the phosphorylation of tank binding kinase 1 and IFN regulatory factor 3. Our findings suggest that the miR-194-FGF2 axis plays a vital role in IAV-induced lung injury, and miR-194 antagonism might be a potential therapeutic target during IAV infection.
Highlights
Influenza A virus (IAV) infection is the leading cause of pneumonia-related deaths worldwide (Herold et al, 2015)
We previously reported that administration of recombinant FGF2 protein markedly reduced mortality and the severity of lung injury in a preclinical model of influenza A virus (IAV) infection
We investigated whether miRNAs could modulate FGF2 in IAV-induced acute lung injury (ALI)
Summary
Influenza A virus (IAV) infection is the leading cause of pneumonia-related deaths worldwide (Herold et al, 2015). IAV infection exposes the host cell to single-stranded genomic RNA and double-stranded RNA intermediates of viral replication, which are recognized by endosomal toll-like receptor (TLR) 3 or TLR7 (Rehwinkel et al, 2010) and the cytoplasmic RNA helicase retinoic acid inducible gene I (RIG-I) (Pichlmair et al, 2006); such recognition drives the activation of antiviral responses during viral infection. Binding of viral RNA to the RIG-I helicase domains triggers its interaction with mitochondria-associated antiviral signaling protein (MAVS), which leads to the production of proinflammatory cytokines downstream of activation nuclear factor kappa-light-chain-enhancer miR-194 Inhibits Innate Antiviral Immunity of activated B cells beta, and the production of type I IFNs and IFN-stimulated genes via nuclear translocation of IFN regulatory transcription factor 3 (IRF3) (Durbin et al, 2013; Iwasaki and Pillai, 2014; Liu et al, 2015; Tavares et al, 2017). The mechanisms underlying the regulation of this pathway require further characterization (Weber-Gerlach and Weber, 2016)
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