The parameters of tissue-resident macrophage autonomy

巨噬细胞是存在于人体组织中的免疫细胞。在正常的日常生活中，这些细胞在维持组织健康方面发挥着关键作用，例如抵御细菌，清除老化和垂死的细胞，以防止不必要的炎症和自身免疫，并且不断发现新的和意想不到的功能。巨噬细胞在几乎所有疾病过程中都起着至关重要的作用，因此它们本身也是治疗策略的关键靶点。因此，了解巨噬细胞是如何在组织内产生和维持的是很重要的，因为这将使我们能够适当地设计出方法来干预它们造成损害的情况，或者在它们有益的情况下促进它们的数量。像大多数免疫细胞一样，组织巨噬细胞被认为是从血液中循环的骨髓来源的细胞中不断补充的。最近，我们已经开始理解，虽然一些巨噬细胞在炎症期间来自血液，但那些驻留在正常健康组织中的巨噬细胞可以在不招募血细胞的情况下存活很长时间。即使在疾病期间，组织中的常驻细胞似乎也会自我再生，以保持与被招募的血液群体的区别。这种独立性的一个原因是血液和组织巨噬细胞具有高度不同的，可能相反的功能，这一假设正在被新的研究证实。到目前为止，大多数研究的重点主要集中在血液来源的巨噬细胞上，但是在炎症期间靶向血液巨噬细胞的策略也可能对常驻巨噬细胞群体产生意想不到的有害影响。因此，本提案的目标是确定常驻巨噬细胞如何维持其独立性，并确定这种独立性是否随着年龄或反复慢性炎症而恶化，以及确定当常驻巨噬细胞被血源性细胞取代时，组织环境中可能发生的功能变化。第一个实验目标是确定是否所有的组织巨噬细胞都具有相同的再生和长期存活能力，或者是否存在一个层次结构，即位于顶端的少数细胞（称为干细胞）寿命很长，并产生更多的细胞，这些细胞在组织中执行大多数重要功能，但再生能力有限。我们目前对干细胞的理解是，它们分裂相对较少，以防止它们获得DNA突变和染色体改变，从而导致细胞老化、衰竭或癌变。发现是否所有组织巨噬细胞都具有相同的自我更新能力，可能会导致未来的研究，以确定细胞内防止衰老但同时允许再生的机制。或者，鉴定干细胞样细胞将提供在疾病期间扩大或收缩常驻巨噬细胞池的靶标。我还计划探索常驻巨噬细胞的再生能力是否存在自然限制，如果存在，这是否会导致血细胞的替代和组织生理学的变化。这项研究可能有助于揭示组织衰老的过程，但也与慢性疾病有关，在慢性疾病中，重复的激活和更新周期可能导致这些细胞加速衰竭。衰老与慢性疾病密切相关，慢性炎症导致衰老速度加快，老年人非消解性炎症发生率更高。通过研究组织巨噬细胞的起源如何随年龄和慢性疾病而改变，我们可以确定连接这两个过程的途径。

Macrophages are immune cells that reside within the tissues of the body. In normal every-day life these cells play key roles in maintaining healthy tissues, for example guarding against bacteria and clearing away old and dying cells to prevent unwanted inflammation and autoimmunity, and new and unexpected functions are continually being discovered. Macrophages are also of central importance to almost every disease process, and thus are themselves key targets of therapeutic strategies. Therefore, it is important that we understand how macrophages are generated and maintained within the tissues as this will allow us to properly devise ways to intervene in situations where they are damaging or promote their numbers where they are beneficial. Like most immune cells, it was thought that tissue macrophages were continually replenished from bone marrow-derived cells that circulate in the blood. Recently, we have begun to understand that while some macrophages come from the blood during inflammation, those that reside in normal healthy tissues survive for long periods without recruiting blood cells into their ranks. Even during disease it appears that resident cells self-regenerate in the tissues in order to remain distinct from the recruited blood population. One reason for such independence is that blood and tissue macrophages have highly distinct and possibly opposing functions, a hypothesis that is being borne out by new research. Until now the focus of most research has largely been on blood-derived macrophages, but strategies that target blood macrophages during inflammation may also result in unintended and detrimental effects on the resident macrophage population. Thus, the goals of this proposal are to establish how resident macrophages maintain their independence and determine if this independence deteriorates with age or repeated chronic inflammation, and to identify the functional changes that may occur in the tissue environment should resident macrophages be replaced by blood-derived cells. The first experimental aim is to determine whether all tissue macrophages have the same ability to regenerate and survive long term, or whether a hierarchy exists whereby a few cells at the top, known as stem cells, are very long lived and give rise to the more numerous cells that carry out most of the important functions in the tissue but have limited regenerative capacity. Our current understanding of stem cells is that they divide relatively infrequently to prevent them acquiring DNA mutations and chromosome changes that result in cells becoming aged, exhausted or cancerous. Discovering if all tissue macrophages have an equal capacity to self-renew could lead to future research to identify those mechanisms within the cell that prevent ageing but at the same time allow regeneration. Alternatively, identification of a stem-like cell would provide a target to expand or contract the resident macrophage pool during disease. I also plan to explore whether there is a natural limit to the extent that resident macrophages can regenerate, and if so, whether this leads to replacement by blood cells and a change in tissue physiology. This research may help to unravel the processes involved in tissue ageing, but is also pertinent to chronic disease in which repeated cycles of activation and renewal could lead to the accelerated exhaustion of these cells. Ageing and chronic disease are intimately related, with chronic inflammation leading to faster ageing, and a greater incidence of non-resolving inflammation in the elderly. By examining how the origin of tissue macrophage may change with age and chronic disease we may identify a pathway that links these two processes.