The parameters of tissue-resident macrophage autonomy

组织驻留巨噬细胞自主性的参数

• 批准号: MR/L008076/1
• 负责人: Stephen Jenkins
• 金额: $ 61.23万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL008076%2F1
• 关键词: parameters; tissue; resident; macrophage; autonomy

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.

巨噬细胞是存在于身体组织内的免疫细胞。在正常的日常生活中，这些细胞在维持健康的组织中发挥着关键作用，例如防止细菌和清除旧的和垂死的细胞，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。巨噬细胞对几乎每种疾病过程都至关重要，因此本身就是治疗策略的关键靶点。因此，重要的是我们要了解巨噬细胞是如何在组织内产生和维持的，因为这将使我们能够适当地设计方法来干预它们正在破坏或促进它们的数量的情况。像大多数免疫细胞一样，人们认为组织巨噬细胞不断从血液中循环的骨髓来源的细胞中补充。最近，我们开始了解到，虽然一些巨噬细胞在炎症期间来自血液，但那些存在于正常健康组织中的巨噬细胞可以长期存活，而不会招募血细胞进入它们的行列。即使在疾病期间，似乎驻留细胞在组织中自我再生，以保持与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功能，可能是相反的功能，这一假设正在被新的研究所证实。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保持其独立性，并确定这种独立性是否随着年龄或反复慢性炎症而恶化，并确定常驻巨噬细胞被血液来源的细胞取代时组织环境中可能发生的功能变化。第一个实验目的是确定所有组织巨噬细胞是否具有相同的再生和长期存活的能力，或者是否存在一个层次结构，其中顶部的一些细胞（称为干细胞）非常长寿，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，它们相对不频繁地分裂，以防止它们获得DNA突变和染色体变化，从而导致细胞老化，疲惫或癌变。发现所有组织巨噬细胞是否都具有同等的自我更新能力可能会导致未来的研究来确定细胞内防止衰老但同时允许再生的机制。或者，干细胞样细胞的鉴定将提供在疾病期间扩增或收缩驻留巨噬细胞池的靶点。我还计划探索是否有一个自然限制的程度，居民巨噬细胞可以再生，如果是这样，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，反复的激活和更新周期可能导致这些细胞加速衰竭。衰老和慢性疾病密切相关，慢性炎症导致更快的衰老，老年人中非消退性炎症的发生率更高。通过研究组织巨噬细胞的起源如何随着年龄和慢性疾病而变化，我们可以确定连接这两个过程的途径。

项目成果

Mucins shed from the laminated layer in cystic echinococcosis are captured by Kupffer cells via the lectin receptor Clec4F

• DOI: 10.1101/2022.10.06.511139
• 发表时间: 2023-03
• 期刊: bioRxiv
• 作者: A. A. Barrios-A.;Camila Mouhape;Leonard Schreiber;Linyun Zhang;J. Nell;Mariana Suárez-Martins;G. Schlapp;M. N. Meikle;A. P. Mulet;T. Hsu;Shie-Liang Hsieh;G. Mourglia-Ettlin;Carlos González;Martina Crispo;Thomas F. E. Barth;C. Casaravilla;Stephen J. Jenkins;Á. Díaz

Cell origin and niche availability dictate the capacity of peritoneal macrophages to colonize the cavity and omentum.

• DOI: 10.1111/imm.13483
• 发表时间: 2022-08
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Louwe PA;Forbes SJ;Bénézech C;Pridans C;Jenkins SJ
• 通讯作者: Jenkins SJ

Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System.

• DOI: 10.4049/jimmunol.1701488
• 发表时间: 2018-03-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hawley CA;Rojo R;Raper A;Sauter KA;Lisowski ZM;Grabert K;Bain CC;Davis GM;Louwe PA;Ostrowski MC;Hume DA;Pridans C;Jenkins SJ
• 通讯作者: Jenkins SJ

Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.

• DOI: 10.1126/sciimmunol.abc4466
• 发表时间: 2020-06-19
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Bain CC;Gibson DA;Steers NJ;Boufea K;Louwe PA;Doherty C;González-Huici V;Gentek R;Magalhaes-Pinto M;Shaw T;Bajénoff M;Bénézech C;Walmsley SR;Dockrell DH;Saunders PTK;Batada NN;Jenkins SJ
• 通讯作者: Jenkins SJ