Mechanisms Regulating Inflammatory Phenotypes in Fetal Macrophages

胎儿巨噬细胞炎症表型的调节机制

• 批准号: 10750088
• 负责人: Lawrence S Prince
• 金额: $ 40.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750088
• 关键词: Adopted; Adult; Agonist; Alveolar Macrophages; Anti-Inflammatory Agents; Antigens; Binding; Birth; Brain; Cell surface; Cells; Circulation; Complex; Computer Analysis; Computer Models; Cues; Data; Data Set; Development; Disease; Enhancers; Epithelium; Fetal Development; Fetal Liver; Fetal Lung; Fetal Tissues; Fetus; Gene Expression; Gene Expression Profile; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune; Immune Tolerance; Immune system; Immunity; Immunology; Infant; Infection; Inflammation; Inflammatory; Injury; Innate Immune Response; Investigation; Knockout Mice; Kupffer Cells; Labor Onset; Liver; Lung; Machine Learning; Macrophage; Maps; Measures; Microbe; Modeling; Molecular; Mothers; Multiomic Data; Mus; Myelogenous; NF-kappa B; Natural Immunity; Neonatal; Newborn Infant; Nuclear Receptors; Organ; Organism; Pathogenesis; Pathway interactions; Pattern; Phenotype; Population; Pregnancy; Property; Proteomics; Research Personnel; Resolution; Role; Signal Transduction; System; Testing; Time; Tissues; Travel; Yolk Sac; cell injury; cytokine; deep learning model; developmental immunology; diverse data; experimental study; fetal; fetal blood; fighting; model development; multidisciplinary; multiple omics; novel; pathogen; pathogenic microbe; postnatal; postnatal period; promoter; response; single cell analysis; trafficking

Summary Macrophages are among the earliest immune cells present during fetal development. Different populations of macrophages have distinct functions, with early yolk sac derived macrophages having an immune tolerant function and later liver derived macrophages having a more robust inflammatory profile. In the mouse lung, the inflammatory profile of liver derived macrophages increases late in development and peaks around the time of birth. This pro-inflammatory phenotype of fetal macrophages conflicts with previous notions that the fetal immune system resides solely in a tolerant state. Inflammatory macrophages may function to protect the developing fetus and newborn from pathogens encountered right at birth, but might also contribute to inflammatory disease pathogenesis, particularly in infants born preterm. We hypothesize that newly formed macrophages arising from the fetal liver are programmed for inflammation via the IKKb/NF-kB pathway. However, once macrophages travel to various organs in the developing fetus, they may adopt tissue-specific features. This proposal will use state of the art, complementary approaches to measure developmental changes in the immune signature of fetal macrophages within developing mouse tissues. Experiments using knockout mice will test if canonical IKKb/NF-kB signaling is required for the pro-inflammatory phenotype. While the myelopoietic cytokine GM-CSF is known to promote alveolar macrophage differentiation in the lung after birth, our preliminary data suggest it may also regulate the inflammatory phenotype in fetal lung macrophages. Studies using Csf2 (the gene encoding GM-CSF) knockout mice will test the requirement of GM-CSF on the developing lung immune system and specifically macrophages. The project will bring together experts in developmental immunology and computational modeling and employ novel, cutting edge approaches to complex systems immunology. The results generated by this proposal will fill a significant gap in our understanding of the fetal immune system and the unique functional properties of macrophages protecting newborns.

概括 巨噬细胞是胎儿发育过程中最早出现的免疫细胞之一。不同人群 巨噬细胞具有独特的功能，早期卵黄囊衍生的巨噬细胞具有免疫耐受性 功能和后来的肝源性巨噬细胞具有更强大的炎症特征。在小鼠肺中， 肝源性巨噬细胞的炎症特征在发育后期增加，并在发育过程中达到峰值 诞生。胎儿巨噬细胞的这种促炎表型与之前的观点相冲突，即胎儿巨噬细胞 免疫系统仅处于耐受状态。炎症巨噬细胞可能起到保护 发育中的胎儿和新生儿受到出生时遇到的病原体的影响，但也可能导致 炎症性疾病的发病机制，尤其是早产儿。我们假设新成立的 胎儿肝脏产生的巨噬细胞通过 IKKb/NF-kB 途径进行炎症编程。 然而，一旦巨噬细胞到达发育中胎儿的各个器官，它们可能会采用组织特异性 特征。该提案将使用最先进的补充方法来衡量发展 发育中的小鼠组织内胎儿巨噬细胞免疫特征的变化。实验使用 基因敲除小鼠将测试促炎表型是否需要典型的 IKKb/NF-kB 信号传导。尽管 众所周知，骨髓生成细胞因子 GM-CSF 可以促进肺内肺泡巨噬细胞的分化。 出生时，我们的初步数据表明它还可能调节胎儿肺巨噬细胞的炎症表型。 使用 Csf2（编码 GM-CSF 的基因）敲除小鼠的研究将测试 GM-CSF 对 发展肺部免疫系统，特别是巨噬细胞。该项目将汇集以下领域的专家 发育免疫学和计算模型，并采用新颖、前沿的方法 复杂系统免疫学。该提案产生的结果将填补我们的重大空白 了解胎儿免疫系统和巨噬细胞保护的独特功能特性 新生儿。