Anti-inflammatory functions for non-transcriptional IRF3

非转录 IRF3 的抗炎功能

• 批准号: 10094550
• 负责人: Saurabh Chattopadhyay
• 金额: $ 47.1万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-08 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094550
• 关键词: Address; Alveolar Macrophages; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; Binding; Biochemical; Cells; Cytosol; Dimerization; Disease model; Engineering; Epithelial Cells; Exhibits; Fatty Liver; 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; Liver diseases; 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; 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

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.

项目摘要/摘要 先天免疫响应是针对微生物感染的第一道防线。病毒感染会引起快速 诱导干扰素（IFN）和IFN诱导的基因，这对于抗病毒防御至关重要。 IFN调节 因子3（IRF3），普遍表达，是IFNβ和抗病毒的关键转录因子 基因。因此，IRF3缺乏会导致对广泛的病毒感染的敏感性。我们有 发现IRF3除了其转录活动外，还具有非转录（NT）功能，以杀死 促凋亡途径RIPA感染病毒的细胞。表达NT-IRF3突变体的敲入小鼠可以安装 在没有抗病毒基因的情况下，抗病毒保护。最近，我们证明了NT-IRF3功能 有助于酒精和非酒精性肝病，进一步增强了身体意义 NT-IRF3。在当前的提案中，我们提出了NT-IRF3抑制NF-κB活性的新功能 炎症基因诱导。我们称IRF3的这种抗炎活性为IRF3-的抑制 介导的NF-κB活性，“ Rika”。我们强大的初步结果表明：（a）IRF3 - / - 细胞，以响应 对于病毒或非病毒刺激，与nf-κB诱导的炎症基因的平均水平相比 WT细胞，（b）IRF3与NF-κB亚基相互作用以抑制其转录活性，并且（c）IRF3 - / - 小鼠 容易受到呼吸道病毒感染的影响，暴露于肺中NF-κB诱导的基因的较高水平。 这些结果导致了我们的中心假设，即nt-irf3被ripa或不依赖转录激活 途径与p65结合，抑制NF-κB诱导的基因，并抑制炎症发病机理。到 使用细胞和条件敲除小鼠模型和呼吸病毒发病机理来解决这个问题，我们 制定两个具体目的：（SA1）研究IRF3在Rika中起作用的分子机制， （SA2）评估RIKA对防止炎症反应和病毒发病机理的贡献。 这些目标的成功完成将描述IRF3的新抗炎功能，这有助于 它的抗病毒功能。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贡献用于防止炎症 发病。我们的结果将很重要，因为描述了IRF3的新抗炎功能 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 这对预防炎症发病机理有影响，超出了病毒感染。