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

项目摘要 组织驻留巨噬细胞在组织内稳态、免疫和疾病中起着重要作用。 因此，解锁他们的生物学是更深入地了解许多人类病理的关键。TRM是独一无二的 来自其他造血细胞，其中大部分相对较短，并不断从 骨髓。取而代之的是，TRMS由卵黄囊和胎儿祖细胞形成，并通过自我维持到成年生活 更新。随着时间的推移，随着每个组织特有的动力学，这些来自胎儿的TRMS在大多数情况下被取代 骨髓来源的单核细胞可能随后获得类似于 它们是胚胎衍生的同类。然而，我们对调节TRMS的普遍因素的理解 跨组织是有限的。细胞新陈代谢是控制细胞分化轨迹的因素之一 不同的免疫细胞亚群，但它如何影响TRM的分化、持久性和功能尚不清楚 进行了详细的研究。我们以前已经确定了多胺代谢及其在氨基酸合成中的作用。 亚硫氨酸作为控制巨噬细胞代谢和激活的中心轴。我们还证明了催产素 合成决定了T细胞承担不同效应命运的能力。这些发现说明了苏氨酚是一种 免疫细胞命运和效应器程序的焦点协调者。然而，竹黄素对组织的贡献 免疫力和TRM维护仍然未知。唯一含有亚硫氨酸的蛋白质是翻译因子。 EIF5A，其中保守的赖氨酸通过亚精胺在两步过程中被酶转化为亚精氨酸。 Hypusated eIF5A促进具有特定序列属性的转录本的翻译。我们在这方面的目标 建议通过解决亚硝胺问题，深入了解TRM生物学在体内平衡和疾病方面的作用 新陈代谢。我们的中心假设是亚硫氨酸调节单核细胞来源的细胞分化为 TRMS和/或它们在组织中的维持，以及通过靶向亚硫氨酸，我们可以调节巨噬细胞 有益于疾病。我们根据已发表的研究和惊人的初步数据得出结论 合成控制巨噬细胞在多个器官中的组织驻留。我们的方法将增加新的洞察力 短命的前体细胞如何发展成长寿的TRMS，执行生命所必需的功能。重要的是 它将确定下丘脑合成是否是在它们影响的上下文中调节TRMS的一条容易处理的途径 疾病，如与肿瘤相关的巨噬细胞和癌症。我们将通过以下方式验证我们的中心假设：1) 研究下丘脑合成在TRM形成和/或维持中的作用，2)探讨其机制 通过它来控制巨噬细胞的组织滞留，以及3)检查 巨噬细胞合成下丘脑有利于抗肿瘤免疫。

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.