Anti-inflammatory functions for non-transcriptional IRF3

项目总结/摘要 先天免疫反应是抵抗微生物感染的第一道防线。病毒感染导致快速 干扰素（IFN）和IFN诱导基因的诱导，这是抗病毒防御的关键。IFN调节 因子3（IRF 3）是诱导IFNβ和抗病毒药物的关键转录因子，广泛表达于大肠杆菌中。 基因.因此，IRF 3缺陷导致对广泛的病毒感染的易感性。我们有 发现IRF 3除了具有转录活性外，还具有非转录（nt）功能，可以杀死 病毒感染的细胞通过促凋亡途径，RIPA。表达nt-Irf 3突变体的基因敲入小鼠， 在缺乏抗病毒基因的情况下的抗病毒保护。最近，我们证明了nt-Irf 3的功能 有助于酒精性和非酒精性肝病，进一步加强生理意义， nt-Irf 3。在目前的建议中，我们提出了一个新的功能，nt-Irf 3抑制NF-κB的活性， 炎症基因诱导我们将IRF 3的这种抗炎活性称为IRF 3的抑制。 介导的NF-κB活性，“RIKA”。我们强有力的初步结果表明：（a）IRF 3-/-细胞，在响应 病毒或非病毒刺激，表达NF-κ B诱导的炎症基因水平升高， Wt细胞，（B）IRF 3与NF-κB亚基相互作用以抑制其转录活性，和（c）Irf 3-/-小鼠 易受呼吸道病毒感染的小鼠，肺中NF-κ B诱导的基因水平较高。 这些结果导致了我们的中心假设，nt-IRF 3，无论是由RIPA激活或转录不依赖 p65，抑制NF-κ B诱导的基因，并抑制炎症发病机制。到 为了解决这个问题，我们使用细胞和条件性基因敲除小鼠模型和呼吸道病毒发病机制， 制定了两个具体目标：（SA 1）研究IRF 3在RIKA中发挥作用的分子机制， 和（SA 2）评价RIKA对预防炎症反应和病毒发病的贡献。 这些目标的成功完成将描绘Irf 3的新抗炎功能，其有助于 抗病毒功能。我们的研究是创新的，因为它使用了新的体外和体内模型来研究 RIKA的分子机制，以及其细胞类型特异性的抗炎作用 发病机制我们的研究结果对于阐明IRF 3新的抗炎功能具有重要意义， 有助于其抗病毒的先天免疫反应，将推动该领域与一个新的功能分支的IRF 3 这在预防炎症发病机制方面有意义，而不仅仅是病毒感染。

Project Summary/Abstract The innate immune response is the first line of defense against microbial infection. Virus infection causes rapid induction of interferon (IFN) and IFN-induced genes, which are critical for antiviral defense. IFN regulatory factor 3 (IRF3), expressed ubiquitously, is the key transcription factor for the induction of IFNβ and the antiviral genes. Therefore, IRF3 deficiency leads to susceptibility to a wide range of virus infections. We have discovered that IRF3, in addition to its transcriptional activity, has a non-transcriptional (nt) function, to kill the virus-infected cells by a pro-apoptotic pathway, RIPA. Knock-in mice, expressing nt-Irf3 mutant, can mount antiviral protection in the absence of antiviral genes. Recently, we demonstrated that nt-Irf3 functions contribute to alcoholic and non-alcoholic liver diseases, further strengthening the physiological significance of nt-Irf3. In the current proposal, we present a new function for nt-Irf3 to inhibit the NF-κB activity and the inflammatory gene induction. We termed this anti-inflammatory activity of IRF3 as Repression of IRF3- mediated NF-κB Activity, “RIKA”. Our strong preliminary results demonstrate that: (a) IRF3-/- cells, in response to viral or non-viral stimulation, express elevated levels of NF-κB-induced inflammatory genes compared to the Wt cells, (b) IRF3 interacts with the NF-κB subunit to inhibit its transcriptional activity, and (c) the Irf3-/- mice that are susceptible to respiratory virus infection, exhibit higher levels of NF-κB-induced genes in the lungs. These results led to our central hypothesis that nt-IRF3, activated by either RIPA or transcription-independent pathway, binds to p65, inhibiting the NF-κB-induced genes, and suppressing inflammatory pathogenesis. To address this, using cellular and conditional knockout mouse models and respiratory virus pathogenesis, we formulate two specific aims: (SA1) Investigate the molecular mechanisms by which IRF3 functions in RIKA, and (SA2) Evaluate the contribution of RIKA to prevent inflammatory responses and viral pathogenesis. Successful completion of these aims will delineate a new anti-inflammatory function of Irf3 that contributes to its antiviral functions. Our research is innovative because it uses the novel in vitro and in vivo models to study the molecular mechanism of RIKA, and its cell type-specific contribution to protect against inflammatory pathogenesis. Our results will be significant as delineating a new anti-inflammatory function for IRF3 that contributes to its antiviral innate immune responses will advance the field with a new functional branch of IRF3 that has implications in preventing inflammatory pathogenesis, beyond viral infection.