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 先天免疫反应是抵御微生物感染的第一道防线。病毒感染导致快速 诱导干扰素和干扰素诱导的基因，这是抗病毒防御的关键。干扰素调节 因子3(Irf3)是诱导干扰素β和抗病毒作用的关键转录因子，广泛表达。 基因。因此，IRF3缺乏导致对多种病毒感染的易感性。我们有 发现IRF3除了转录活性外，还具有非转录(NT)功能，可以杀死 通过促凋亡途径RIPA感染病毒的细胞。表达NT-IRF3突变体的敲入小鼠可以 在缺乏抗病毒基因的情况下进行抗病毒保护。最近，我们演示了NT-IRF3的功能 促进酒精性和非酒精性肝病，进一步加强生理学意义 NT-IRF3.在目前的方案中，我们提出了NT-irf3的一个新功能，以抑制NF-κB的活性和 炎性基因诱导。我们将IRF3的这种抗炎活性称为抑制IRF3- 介导的核因子-κB活性，“Rika”。我们强有力的初步结果表明：(A)IRF3-/-细胞，作为对 对病毒或非病毒刺激，表达较高水平的NF-κB诱导的炎症基因 WT细胞，(B)irf3与核因子-κB亚基相互作用以抑制其转录活性，以及(C)irf3-/-小鼠 易受呼吸道病毒感染的患者，在肺部表现出较高水平的NF-κB诱导基因。 这些结果导致了我们的中心假设，NT-IRF3由RIPA或转录独立激活 途径，结合p65，抑制核因子-κB诱导的基因，抑制炎症发病。至 为了解决这个问题，利用细胞和条件基因敲除小鼠模型和呼吸道病毒发病机制，我们 制定两个具体目标：(SA1)研究IRF3在Rika中发挥作用的分子机制， 和(SA2)评估Rika在预防炎症反应和病毒致病方面的贡献。 这些目标的成功实现将勾勒出IRF3的新的抗炎功能，有助于 它的抗病毒功能。我们的研究具有创新性，因为它使用了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抗炎作用 发病机制。我们的结果将对描绘IRF3的新的抗炎功能具有重要意义 对其抗病毒先天免疫反应的贡献将推动IRF3一个新的功能分支的研究 这不仅在病毒感染方面，而且在预防炎症发病方面也有意义。