The Role of the Amino Acid Hypusine in the Maintenance and Function of Tissue-Resident Macrophages

项目摘要 组织驻留巨噬细胞（TRM）在组织稳态、免疫和疾病中起着重要作用。 因此，解开他们的生物学是获得许多人类病理学更深入知识的关键。TRM是独一无二的 从其他造血细胞，其中大多数是相对短暂的，并不断补充， 骨髓相反，TRM由卵黄囊和胎儿祖细胞形成，并通过自我修复持续到成年。 退款随着时间的推移，并且随着每个组织的特定动力学，这些胎儿来源的TRM在大多数组织中被替换。 骨髓来源的单核细胞，随后可能获得类似的转录谱， 它们的胚胎衍生物。然而，我们对调节TRM的普遍因素的理解 跨组织的能力是有限的细胞代谢是一个这样的因素，其支配细胞的分化轨迹。 各种免疫细胞亚群，但它如何塑造TRM分化，持久性和功能还有待进一步研究。 详细研究我们以前确定了多胺代谢，及其在氨基酸合成中的作用， 羟腐胺赖氨酸作为控制巨噬细胞代谢和活化的中心轴。我们还发现羟腐胺赖氨酸 合成指导T细胞采取不同效应物命运的能力。这些发现阐明了羟腐胺赖氨酸作为一种 免疫细胞命运和效应程序的焦点协调员。然而，羟腐胺赖氨酸如何有助于组织 免疫和TRM维持仍然未知。含有羟腐胺赖氨酸的唯一蛋白质是翻译因子 eIF 5A，其中保守的赖氨酸通过亚精胺在两步过程中酶促转化为羟腐胺赖氨酸。 Hypusinated eIF 5A促进具有特定序列特性的转录物的翻译。我们的目标是 建议是通过解决羟腐胺赖氨酸来深入了解TRM生物学在稳态和疾病中的作用 新陈代谢.我们的中心假设是羟腐胺赖氨酸调节单核细胞衍生的细胞分化为 TRM和/或它们在组织中的维持，并且通过靶向羟腐胺赖氨酸，我们可以调节巨噬细胞， 有益于疾病。我们基于我们已发表的工作和惊人的初步数据，表明羟腐胺赖氨酸 合成控制跨多个器官的巨噬细胞组织驻留。我们的方法将为以下方面增添新的见解 短寿命的前体细胞如何发育成长寿命的TRM，执行生命所必需的功能。重要的是， 它将确定羟腐胺赖氨酸合成是否是调节TRM的易处理途径， 疾病，如与肿瘤相关的巨噬细胞和癌症。我们将测试我们的中心假设，1） 研究羟腐胺赖氨酸合成在TRM形成和/或维持中的作用，2）探索其机制 羟腐胺赖氨酸通过其控制巨噬细胞组织驻留，以及3）检查是否操纵 巨噬细胞中羟腐胺赖氨酸的合成有益于抗肿瘤免疫。

Project Summary Tissue-resident macrophages (TRMs) play fundamental roles in tissue homeostasis, immunity, and disease. Thus, unlocking their biology is key to gaining a deeper knowledge of many human pathologies. TRMs are unique from other hematopoietic cells, most of which are comparatively short-lived and continually replenished from the bone marrow. Instead, TRMs form from yolk sac and fetal progenitors and persist into adult life through self- renewal. Over time, and with kinetics specific to each tissue, these fetal-derived TRMs are replaced in most tissues by bone marrow-derived monocytes, which may subsequently acquire a similar transcriptional profile to their embryonic-derived counterparts. However, our understanding of universal factors that regulate TRMs across tissues is limited. Cellular metabolism is one such factor that governs the differentiation trajectories of various immune cell subsets, but how it shapes TRM differentiation, persistence, and function has yet to be studied in detail. We previously identified polyamine metabolism, and its role in the synthesis of the amino acid hypusine as a central axis governing macrophage metabolism and activation. We also showed that hypusine synthesis directs the ability of T cells to take on distinct effector fates. These findings illuminated hypusine as a focal coordinator of immune cell fate and effector programs. However, how hypusine contributes to tissue immunity and TRM maintenance remains unknown. The sole protein to contain hypusine is the translation factor eIF5A, in which a conserved lysine is enzymatically converted to hypusine in a two-step process via spermidine. Hypusinated eIF5A promotes the translation of transcripts with specific sequence properties. Our goal in this proposal is to gain deep understanding of TRM biology in homeostasis and disease by addressing hypusine metabolism. Our central hypothesis is that hypusine regulates the differentiation of monocyte-derived cells into TRMs and/or their maintenance in tissues, and that by targeting hypusine we can modulate macrophages to benefit disease. We base this on our published work and striking preliminary data suggesting that hypusine synthesis controls macrophage tissue-residency across multiple organs. Our approach will add new insight into how short-lived precursor cells develop into long-lived TRMs that carry out functions essential for life. Importantly, it will establish if hypusine synthesis is a tractable route to modulate TRMs in contexts where they influence disease, such as with tumor-associated macrophages and cancer. We will test our central hypothesis by, 1) investigating the role of hypusine synthesis in TRM formation and/or maintenance, 2) probing the mechanisms through which hypusine governs macrophage tissue-residency, and 3) examining whether manipulating hypusine synthesis in macrophages benefits anti-tumor immunity.