Mechanisms Regulating Inflammatory Phenotypes in Fetal Macrophages

摘要 巨噬细胞是胎儿发育过程中最早出现的免疫细胞之一。不同的种群 巨噬细胞具有不同的功能，早期卵黄囊来源的巨噬细胞具有免疫耐受性。 功能和后来的肝脏来源的巨噬细胞具有更强大的炎症特征。在小鼠的肺里， 肝源性巨噬细胞的炎症特征在发育后期增加，并在 出生。胎儿巨噬细胞的这种促炎表型与先前关于胎儿 免疫系统只处于一种耐受状态。炎性巨噬细胞可能起到保护 从出生时就遇到的病原体发育成胎儿和新生儿，但也可能有助于 炎症性疾病的发病机制，尤其是在早产儿中。我们假设新成立的 来自胎肝的巨噬细胞通过IKKB/NF-kB途径被编程为炎症反应。 然而，一旦巨噬细胞移动到发育中的胎儿的不同器官，它们可能会采用组织特异性 功能。这项提案将使用最先进的、互补的方法来衡量发展 发育中的小鼠组织内胎儿巨噬细胞免疫信号的变化。使用以下工具进行实验 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。而当 已知骨髓细胞因子GM-CSF可促进肺组织中的肺泡巨噬细胞分化 出生后，我们的初步数据表明，它也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)基因敲除小鼠的研究将测试GM-CSF对 发展肺免疫系统，特别是巨噬细胞。该项目将把专家聚集在一起 发展免疫学和计算建模，并采用新的尖端方法来 复杂系统免疫学。这项提议产生的结果将填补我们在 了解胎儿免疫系统和巨噬细胞保护的独特功能 新生儿。

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.