Study the role of hnRNP I in regulating IRAK1-dependent TLR signaling in intestinal crypt cells

研究hnRNP I在调节肠隐窝细胞IRAK1依赖性TLR信号传导中的作用

• 批准号: 9807122
• 负责人: Wenyan Mei
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-14 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807122
• 关键词: Adult; Allergic; Allergic Disease; Anti-inflammatory; Apoptosis; Autoimmune Diseases; Cancerous; Cell Compartmentation; Cell Proliferation; Cell Survival; Cells; Communicable Diseases; Defect; Disease; Down-Regulation; Early Diagnosis; Economics; Environment; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Foundations; Future; Gastrointestinal tract structure; Health; Heterogeneous-Nuclear Ribonucleoproteins; Homeostasis; Human; IRAK1 gene; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunity; Immunologics; Impairment; Inflammatory; Interleukin-10; Intestinal Mucosa; Intestines; Ligands; Malignant Neoplasms; Mediating; Metabolic; Microbe; Molecular; Mus; Mutant Strains Mice; Natural Immunity; Necrotizing Enterocolitis; Neonatal; Nuclear; Organoids; Personal Satisfaction; Phenotype; Play; Prevention; Proteins; Quality of life; RNA-Binding Proteins; Receptor Signaling; Regulation; Reporting; Role; Shapes; Signal Transduction; Solid; Stem cells; Surface; TLR4 gene; Testing; Toll-like receptors; Transducers; base; cell behavior; commensal microbes; crypt cell; design; experimental study; gut microbiota; host-microbe interactions; human disease; improved; intestinal crypt; intestinal epithelium; intestinal homeostasis; microbial; microbial colonization; microorganism; novel; prevent; sensor

Abstract The intestinal epithelium plays a central role in controlling host-microbe interactions by acting as a physical barrier, a sensor of luminal microorganisms, and a signal transducer of microbial stimulation. This function is largely mediated by Toll-like receptor (TLR) signaling in the intestinal epithelial cells. Increasing evidence indicate that TLR-mediated host-microbe interactions are critical for shaping the host immune system and maintaining intestinal homeostasis. As such, epithelial TLR signaling must be precisely regulated to prevent diseases such as necrotizing enterocolitis, autoimmune disorders, inflammatory diseases, and cancer. Thus, studying mechanisms underlying epithelial TLR signaling regulation is of great importance. Our previous studies reveal that hnRNP I, an RNA-binding protein, is a novel regulator of neonatal intestinal epithelial innate immunity through downregulating IRAK1-mediated TLR signaling. Inspired by this observation, we went on to determine if hnRNP I regulates intestinal epithelial TLR signaling in adulthood, a stage when intestinal epithelial cells have acquired immune tolerance to commensal microbes. We found that loss of hnRNP I in adult intestinal epithelial cells results in severe crypt cell apoptosis and loss of intestinal stem cells, highly resembling defects of TLR4 activation in crypt cells. Strikingly, nuclear accumulation of IRAK1, a key component of TLR4 signaling, is dramatically reduced in the crypt cells. Based on these exciting findings, we formulated the hypothesis that hnRNP I regulates IRAK1-dependent TLR4 signaling in crypt cells to guard crosstalk between crypt cells and luminal microbes. As initial steps to test this hypothesis, we propose to investigate if hnRNP I regulates crypt cell innate immunity through the control of TLR4-mediated signaling. Moreover, we propose to investigate if loss of hnRNP I reduces the immune tolerance of crypt cells to commensal microbes. Completion of the proposed studies will build a solid foundation for our future in-depth mechanistic studies on hnRNP I-dependent TLR signaling regulation, which will likely uncover novel mechanisms important for the control of innate immunity in the intestinal stem cell compartments.

摘要 肠上皮通过充当物理屏障在控制宿主-微生物相互作用中起核心作用。 屏障、管腔微生物的传感器和微生物刺激的信号转换器。此功能 主要由肠上皮细胞中的Toll样受体（TLR）信号传导介导。越来越多的证据 表明TLR介导的宿主-微生物相互作用对于塑造宿主免疫系统至关重要， 维持肠道内环境稳定因此，上皮TLR信号传导必须被精确调节，以防止 疾病如坏死性小肠结肠炎、自身免疫性疾病、炎性疾病和癌症。因此，在本发明中， 研究上皮TLR信号调节的潜在机制是非常重要的。我们以前的 研究表明，hnRNP I是一种RNA结合蛋白，是新生儿肠上皮先天性 通过下调IRAK 1介导的TLR信号传导增强免疫力。受这一观察的启发，我们继续 确定hnRNP I是否在成年期调节肠上皮TLR信号传导，这是肠上皮细胞 上皮细胞获得了对肠道微生物的免疫耐受。我们发现hnRNP I的缺失 成年肠上皮细胞导致严重的隐窝细胞凋亡和肠干细胞丢失， 类似于隐窝细胞中TLR 4活化的缺陷。引人注目的是，IRAK 1的核积累， TLR 4信号传导的组成部分在隐窝细胞中显著减少。基于这些令人兴奋的发现，我们 阐述了hnRNP I调节隐窝细胞中IRAK 1依赖性TLR 4信号传导以保护细胞的假说。 隐窝细胞和管腔微生物之间的相互作用。作为检验这一假设的初步步骤，我们建议 研究hnRNP I是否通过控制TLR 4介导的信号传导调节隐窝细胞先天免疫。 此外，我们建议研究hnRNP I的缺失是否会降低隐窝细胞对 浮游微生物完成建议的研究，将为我们日后深入研究 hnRNP I依赖性TLR信号调节的机制研究，这可能会发现新的 在肠道干细胞隔室中控制先天免疫的重要机制。