Autophagy Negatively Regulated Antiviral Innate Immune Response By Suppressing The Production Of Type?IFN

Innate immunity is the first line for the organism to defense viruses.After entering into the body,virus was recognized by the pattern recognition receptors(PRRs),which rapidly induced innate immune response and produce a mass of type ? interferons(IFNs)as well as proinflammatory cytokines.Type ? interferon can bind to its receptors which located on the cell membrane and induce the expression of antiviral proteins which can then inhibit the replication and infection ability of virus.Due to the pivotal role of type ?interferon,its expression must be controled strictly,which has been a hot research spot in the antiviral immune response these years.Autophagy is a highly conserved homeostasis mechanism which only happened in eukaryotic cells,and is important for cells to resistant to external and internal stimuli.It has been revealed that virus infection could induce the activation of autophagy,but the detailed mechanism is unclear.Therefore,we want to explore how autophagy regulates the antiviral innate immune response.Firstly,we built autophagy-deficient mice in which autophagy associated gene 7(ATG7)was specifically knocked down in myeloid cells with Lysm-Cre.Then,we used VSV(vesicular stomatitis virus)to infect the peritoneal macrophages(PM)separated from the wild type and knock-out mice.We found that the PMs separated from autophagy-deficient mice displayed stronger ability to resist VSV infection.For in vivo experiments,after infected with lethal dose VSV through intraperitoneal injection,autophagy-deficient mice showed higher survival rate,lower degree of lung injury and less viral titers,compared with wild type mice.Because type ? interferon plays an important role in innate antiviral immunity,we further explored whether the strong antiviral effect of autophagy-dificient mice was due to the high level of type ? interferon.After viral infection,we found that the expression of type? interferon was obviously increased in peritoneal macrophages separated fromautophagy-deficient mice compared with that from wild type mice.VSV,as a dsRNAviruse,can activate both TLR3 signnaling pathways and RIG-? signaling pathways,both resulting in type I interferon production.We found that the phosphorylation of IRF3 was enhanced in the PMs separated from autophagy-deficient mice,but the phosphorylation of NF-?B remained unchange.Moveover,the mRNA level of IRF3 was also increased in the PMs separated from autophagy-deficient mice.In briefly,we revealed that autophagy deficiency could result in the increase of IRF3 phosphorylation,which in turn enhanced the expression of type ?interferon,finally improved the antiviral ability of macrophagy.Our study indicates the significant role of autophagy in the regulation of antiviral innate immunity,and may help to provide new strategies for the clinical treatment of viral infections.