Anti-inflammatory functions for non-transcriptional IRF3

非转录 IRF3 的抗炎功能

基本信息

批准号：
10347311
负责人：
Saurabh Chattopadhyay
金额：
$ 46.49万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347311
关键词：
Address Alveolar Macrophages Anti-Inflammatory Agents Antiviral Response Apoptosis Apoptotic Binding Biochemical Cells Cytosol Dimerization Disease model Engineering Epithelial Cells Exhibits Gene Expression Genes Genetic Transcription Goals Human IRF3 gene Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Influenza Innate Immune Response Interferons Knock-in Mouse Knowledge Location LoxP-flanked allele Lung Maps Measures Mediating Microscopic Modeling Molecular Mus Natural Immunity Nuclear Translocation Pathogenesis Pathway interactions Phosphorylation Physiological Predisposition Property Proteins Repression Research Research Personnel Role Sendai virus Stimulus TNF gene TNFRSF5 gene Testing Therapeutic Ubiquitination Viral Viral Pathogenesis Virus Virus Diseases airway epithelium base cell type conditional knockout design domain mapping fatty liver disease gene induction genetic approach in vivo in vivo Model innovation macrophage microbial mouse model mutant non-alcoholic fatty liver disease novel p65 prevent problem drinker respiratory infection virus respiratory virus response three dimensional structure transcription factor

项目摘要

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.

项目概要/摘要先天免疫反应是抵抗病毒快速感染的第一道防线。干扰素 (IFN) 和 IFN 诱导基因的诱导，这对于抗病毒防御至关重要。因子 3 (IRF3) 广泛表达，是诱导 IFNβ 和抗病毒药物的关键转录因子。因此，IRF3缺陷会导致对多种病毒感染的易感性。发现IRF3除了其转录活性外，还具有非转录（nt）功能，可以杀死通过促凋亡途径感染病毒的细胞，表达 nt-Irf3 突变体的 RIPA 小鼠可以安装。最近，我们证明了 nt-Irf3 的功能。有助于酒精性和非酒精性肝病，进一步加强了其生理意义在当前的提案中，我们提出了 nt-Irf3 抑制 NF-κB 活性的新功能。我们将 IRF3 的这种抗炎活性称为 IRF3- 的抑制。介导的 NF-κB 活性，“RIKA”，我们强有力的初步结果表明：(a) IRF3-/- 细胞做出反应。与病毒或非病毒刺激相比，NF-κB 诱导的炎症基因表达水平升高 Wt 细胞，(b) IRF3 与 NF-κB 亚基相互作用以抑制其转录活性，(c) Irf3-/- 小鼠易受呼吸道病毒感染的人，肺部表现出较高水平的 NF-κB 诱导基因。这些结果引出了我们的中心假设，即 nt-IRF3 由 RIPA 或转录无关激活途径，结合 p65，抑制 NF-κB 诱导基因，抑制炎症发病机制。为了解决这个问题，我们使用细胞和条件敲除小鼠模型和呼吸道病毒发病机制制定两个具体目标：（SA1）研究IRF3在RIKA中发挥作用的分子机制， (SA2) 评估 RIKA 对预防炎症反应和病毒发病机制的贡献。这些目标的成功完成将描绘出 Irf3 的新抗炎功能，该功能有助于我们的研究具有创新性，因为它使用新颖的体外和体内模型来研究。 RIKA 的分子机制及其细胞类型特异性对预防炎症的贡献我们的结果对于描述 IRF3 的新抗炎功能具有重要意义。有助于其抗病毒先天免疫反应将通过 IRF3 的新功能分支推动该领域的发展除了病毒感染之外，这对预防炎症发病机制也有影响。