Dissecting interplay between electrophilic stress and IkBz-driven inflammation

剖析亲电子应激与 IkBz 驱动的炎症之间的相互作用

• 批准号: 10452024
• 负责人: Monika Bambouskova
• 金额: $ 19.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452024
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Address; Affect; Animal Model; Anti-Inflammatory Agents; Autoimmune Diseases; Cell Line; Cells; Cellular Stress Response; Characteristics; Cysteine; Data; Development; Down-Regulation; Elements; Epithelial Cells; Family; Foundations; Future; Genes; Genetic; Genetic Transcription; Genetic study; Health; Human; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Interleukin-12; Interleukin-17; Interleukin-6; Investigation; Macrophage Activation; Mediating; Medical Genetics; Messenger RNA; Metabolic; Molecular; Mus; Nature; Pathology; Pathway interactions; Pharmacology; Pneumococcal Infections; Population Genetics; Production; Proteins; Psoriasis; RNA-Binding Proteins; Regulation; Regulatory Element; Role; Signal Transduction; Stress; Sulfhydryl Compounds; Susceptibility Gene; T-Lymphocyte; TNF gene; Toll-like receptors; Transcript; Translational Regulation; Translational Repression; Translations; Untranslated Regions; Up-Regulation; arm; biological adaptation to stress; cytokine; genetic approach; immune activation; immunoregulation; in vivo; macrophage; member; mouse model; novel; novel therapeutic intervention; novel therapeutics; operation; programs; response; sensor; transcription factor; treatment strategy; trigger point

Abstract Electrophilic stress is a broad phenomenon caused by compounds that are reactive to thiol groups (-SH), such as cysteine residues within cellular proteins. We found that electrophilic stress response induced by dimethyl itaconate (DI), a derivative of the metabolite itaconate, mediates a strong, yet very selective inhibitory effect on the immune activation. In macrophages, DI treatment downregulates production of a subset of cytokines such as IL-6 or IL-12 but does not affect other cytokines such as TNF. We found that this selective effect occurs through inhibition of IκBζ, a transcription factor of the NF-κB family, which is commonly induced during immune activation. IκBζ selectively regulates inflammation in several important contexts: (1) in macrophages, IκBζ regulates the secondary transcriptional response to toll-like receptor stimulation and its deficiency leads to defective production of a subset of cytokines such as IL-6 and IL-12, but not TNF; (2) in epithelial cells, IκBζ is a primary regulator of the transcriptional response to IL-17; (3) in T-cells, it is an indispensable transcription factor facilitating Th17 polarization. Importantly, medical and population genetics studies have identified NFΚBIZ (the gene encoding IκBζ) as a major susceptibility locus for psoriasis, an IL-17-associated autoimmune condition. We have demonstrated that in vivo administration of DI completely ameliorates development of pathology in a mouse model of psoriasis. Therefore, a deeper understanding of the connection between IκBζ and electrophilic stress has the strong potential to uncover novel therapeutic avenues for treatment of autoimmune conditions, such as psoriasis. Moreover, although the major studied cellular response to electrophilic stress is the Keap1/Nrf2 pathway, we show that the effect of DI on IκBζ is independent of Nrf2. Our preliminary data suggest the existence of a discrete Nrf2-independent molecular pathway starting at Keap1 engagement by electrophiles and culminating in selective inhibition of IκBζ translation. Defining the mechanistic details of this pathway will deepen the general understanding of immune regulation and will provide novel therapeutic strategies in autoimmune diseases driven by the IκBζ-IL-17 axis. We aim to uncover key members and mechanisms of this pathway using the following converging strategies: 1) define the mechanism of IκBζ inhibition by electrophilic stress at the level of Keap1 and 2) define the mechanism of translational regulation of Nfkbiz mRNA in conditions of electrophilic stress. Completion of the proposed Aims will lay the foundation for future detailed in vitro and in vivo studies of the novel regulator/regulators of the IκBζ activation program. Ultimately, we aim to study the role of the novel IκBζ regulators identified by this proposal in the context of an inflammatory condition such as psoriasis, which will be the subject of a future R01 application.

摘要