Diet-derived oxysterols shape intestinal B cell fate by controlling intracellular cholesterol metabolism

饮食来源的氧甾醇通过控制细胞内胆固醇代谢来塑造肠道 B 细胞的命运

• 批准号: 10299176
• 负责人: Andrea Reboldi
• 金额: $ 46.72万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-25 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299176
• 关键词: 16S ribosomal RNA sequencing; 25-hydroxycholesterol; Adaptive Immune System; Antibiotics; Antibodies; Antibody Formation; Antibody Response; Antigens; Area; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Lymphocytes; Bacterial Antigens; Bile Acids; Binding Proteins; Biological Assay; Biological Availability; Biological Process; Cells; Cholesterol; Cholesterol Homeostasis; Clone Cells; Communities; Complex; Couples; Cues; Data; Diet; Dietary Cholesterol; Dietary Intervention; Environment; Exposure to; Follicular Dendritic Cells; Foundations; Gastrointestinal tract structure; Gene Expression Profile; Generations; Genes; Genetic Transcription; Helper-Inducer T-Lymphocyte; Homeostasis; Immune; Immune system; Immunology; Impairment; Individual; Intervention; Intestines; Lead; Link; Lipids; Maintenance; Maps; Mediating; Memory B-Lymphocyte; Metabolic; Metabolism; Modeling; Molecular; Mus; Nature; Output; Oxides; Pathway interactions; Peripheral; Pharmacology; Phenocopy; Plasma Cells; Play; Process; Production; Reaction; Reagent; Regulation; Response Elements; Role; Shapes; Source; Spleen; Sterols; Stimulus; Stromal Cells; Structure of germinal center of lymph node; Testing; Transcriptional Regulation; Work; adaptive immunity; base; cholesterol absorption; commensal bacteria; dietary; dietary manipulation; draining lymph node; expectation; in vivo; insight; intestinal homeostasis; lipid biosynthesis; lipid metabolism; liquid chromatography mass spectrometry; lymph nodes; machine learning method; microbial; microbiome; microorganism antigen; novel; oxysterol binding protein; plasma cell differentiation; prevent; response; transcription factor; transcriptome sequencing

Abstract B lymphocytes in the gastrointestinal tract are constantly stimulated by commensals microbial antigens. In order to prevent commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep process of B cell proliferation and selection in the germinal center, which eventually gives rise to either antibody secreting plasma cells or memory B cells. Intestinal B cells are also exposed to dietary and microbial metabolites during their activation and differentiation, but how these environmental cues shape B cell fate and antibody response in the gut is poorly understood. Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of individual B cell clones in the gut remains a central question in immunology. Several lines of evidence indicate that metabolic switches act as intrinsic regulators of germinal center B cell response. However, how B cells integrate metabolite sensing with germinal center and antibody response remains undefined to date. In this application we test the hypothesis that the oxysterol 25-HC, an oxidized form of cholesterol, directly controls germinal center B cell response through its interaction with the Sterol Response Element Binding Protein 2 (SREBP2). SREBP2 is a key regulator of intracellular cholesterol homeostasis, and its transcriptional activity in the intestinal germinal center B cells couples lipid metabolism and B cell differentiation in the intestine. We also hypothesize that follicular dendritic cells (FDCs), stromal cells which are located in the germinal center, produce 25-HC in response to dietary cholesterol and microbiome, therefore linking rapidly changing intestinal homeostasis to B cell fate. Accumulating evidence indicates that 25-HC controls SREBP2 processing, but the implication for this cross talk in B cells in the gut has not been investigated so far. Our aims are: 1) To test the hypothesis that SREBP2 activity controls germinal center B cell transcriptional profile and B cell fate; and 2) To define the environmental and cellular cues that regulate 25-HC niche. The proposed studies examine a very poorly understood crosstalk between oxidized form of cholesterol, intestinal metabolism and adaptive immune system activation. It is our expectation that these studies will increase our understanding of how intestinal metabolism shapes B cell responses and adaptive immunity. Furthermore, these studies will provide a foundation for better understanding of the relationship between lipid metabolism and differentiation in immune cells.

摘要 胃肠道中的B淋巴细胞不断受到肠道微生物抗原的刺激。为了 为了防止肠道生长和维持肠道内环境稳定，B细胞需要快速的抗体反应 对抗细菌抗原。 为了实现这一任务，体液免疫系统依赖于B细胞增殖的复杂多步骤过程， 在生发中心进行选择，最终产生分泌抗体的浆细胞或记忆B细胞。 肠B细胞在其活化和分化过程中也暴露于饮食和微生物代谢物，但 这些环境因素如何影响肠道中B细胞的命运和抗体反应还知之甚少。 因此，阐明内在调节单个B细胞命运和功能的基本机制， 肠道中的克隆仍然是免疫学的中心问题。 几条证据表明，代谢开关作为内源性调节剂的生发中心B细胞的反应。 然而，B细胞如何将代谢物传感与生发中心和抗体反应整合在一起， 约会 在本申请中，我们测试了氧化固醇25-HC（胆固醇的氧化形式）直接控制 通过其与固醇应答元件结合蛋白2（SREBP 2）的相互作用，参与衰老中心B细胞应答。 SREBP 2是细胞内胆固醇稳态的关键调节因子，其在肠道中的转录活性 生殖中心B细胞偶联肠中的脂质代谢和B细胞分化。我们还假设， 滤泡树突状细胞（follicular dendritic cells，FDC）是位于生发中心的基质细胞， 饮食胆固醇和微生物组，因此将快速变化的肠道稳态与B细胞命运联系起来。 越来越多的证据表明，25-HC控制SREBP 2的加工，但B中这种串扰的含义 到目前为止还没有研究过肠道细胞。 我们的目的是：1）验证SREBP 2活性控制生发中心B细胞转录谱的假设， B细胞命运;和2）确定调节25-HC生态位的环境和细胞线索。 拟议的研究检查了氧化形式的胆固醇、肠内胆固醇和胆固醇之间的一种非常不为人知的串扰。 代谢和适应性免疫系统激活。我们期望这些研究将增加我们的 了解肠道代谢如何塑造B细胞反应和适应性免疫。此外，这些研究 将为更好地理解脂质代谢与分化之间的关系提供基础， 免疫细胞