Protein kinase R (PKR) is a vital component of host innate immunity against viral infection. However, the mechanism underlying inactivation of PKR by influenza A virus (IAV) remains elusive. Here, we found that vault RNAs (vtRNAs) were greatly induced in A549 cells and mouse lungs after infection with IAV. The viral NS1 protein was shown to be the inducer triggering the upregulation of vtRNAs. Importantly, silencing vtRNA in A549 cells significantly inhibited IAV replication, whereas overexpression of vtRNAs markedly promoted the viral replication. Furthermore, in vivo studies showed that disrupting vtRNA expression in mice significantly decreased IAV replication in infected lungs. The vtRNA knockdown animals exhibited significantly enhanced resistance to IAV infection, as evidenced by attenuated acute lung injury and spleen atrophy and consequently increased survival rates. Interestingly, vtRNAs promoted viral replication through repressing the activation of PKR and the subsequent antiviral interferon response. In addition, increased expression of vtRNAs was required for efficient suppression of PKR by NS1 during IAV infection. Moreover, vtRNAs were also significantly upregulated by infections of several other viruses and involved in the inactivation of PKR signaling by these viruses. These results reveal a novel mechanism by which some viruses circumvent PKR-mediated innate immunity.

Influenza A virus (IAV) remains a major public health threat in the world, as indicated by the severe pneumonia caused by its infection annually. Interleukin-6 (IL-6) involved excessive inflammatory response to IAV infection profoundly contributes to the virus pathogenesis. However, the precise mechanisms underlying such a response are poorly understood. Here we found from both in vivo and in vitro studies that IAV not only induced a surge of IL-6 release, but also greatly upregulated expression of suppressor of cytokine signaling-3 (SOCS3), the potent suppressor of IL-6-associated signal transducer and activator of transcription 3 (STAT3) signaling. Interestingly, there existed a cytokine-independent mechanism of the robust induction of SOCS3 by IAV at early stages of the infection. Furthermore, we employed SOCS3-knockdown transgenic mice (TG), and surprisingly observed from virus challenge experiments using these mice that disruption of SOCS3 expression provided significant protection against IAV infection, as evidenced by attenuated acute lung injury, a higher survival rate of infected animals and lower viral load in infected tissues as compared with those of wild-type littermates under the same condition. The activity of nuclear factor-kappa B (NFκB) and the expression of its target gene IL-6 were suppressed in SOCS3-knockdown A549 cells and the TG mice after infection with IAV. Moreover, we defined that enhanced STAT3 activity caused by SOCS3 silencing was important for the regulation of NFκB and IL-6. These findings establish a critical role for IL-6-STAT3-SOCS3 axis in the pathogenesis of IAV and suggest that influenza virus may have evolved a strategy to circumvent IL-6/STAT3-mediated immune response through upregulating SOCS3.

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Objective: Despite extensive studies, the precise mechanism underlying spondyloarthritis, especially ankylosing spondylitis, remains elusive. This study aimed to develop an ideal animal model for an insight into mechanism of spondyloarthritis and functional relevance of SOCS3 in spondyloarthritis.Methods: Since SOCS3 is a major regulator of IL23-STAT3 signaling, we generated SOCS3 knockdown transgenic (TG) mice for development of an animal model of spondyloarthritis. A hydrodynamic delivery method was employed to deliver minicircle DNA expressing IL23 (mc-IL23) into wild-type (WT) and the TG mice. Knockdown/overexpression systems mediated by lentivirus and retrovirus were used to determine whether SOCS3 regulated osteoblast differentiation.Results: Forced expression of IL23 induced severe joint destruction and extensive bone loss in SOCS3 knockdown TG mice, while this treatment only caused moderate symptoms in WT mice. Furthermore, severe spondyloarthritis was found in IL23-injected TG mice as compared to mild disease observed in WT controls under same condition. Moreover, our studies showed that IL23 promoted osteoblast differentiation via activation of STAT3 pathway and disruption of SOCS3 expression greatly increased phosphorylation of STAT3. In addition, silencing SOCS3 resulted in enhanced osteoblast differentiation through activation of Smad1/5/9 signaling, as evidenced by elevated phosphorylation level of Smad1/5/9. Experiments further demonstrated that SOCS3 interacted with Smad1 and thus suppressed the BMP2-Smad signaling.Conclusions: The results reveal that SOCS3 is involved in IL23-induced spondyloarthritis and acts as a key regulator of osteoblast differentiation, and suggest that SOCS3 knockdown TG mice may be an ideal animal model for further studies of spondyloarthritis.