Inflammation rapidly recruits mammalian GMP and MDP from bone marrow into regional lymphatics.
Inflammation rapidly recruits mammalian GMP and MDP from bone marrow into regional lymphatics.
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DOI：
10.7554/elife.66190
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发表时间：
2021-04-08
期刊：
影响因子：
7.7
通讯作者：
Cancelas JA
中科院分区：
文献类型：
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作者：
Serrano-Lopez J;Hegde S;Kumar S;Serrano J;Fang J;Wellendorf AM;Roche PA;Rangel Y;Carrington LJ;Geiger H;Grimes HL;Luther S;Maillard I;Sanchez-Garcia J;Starczynowski DT;Cancelas JA
先天免疫细胞效应物在全身性炎症中被积极消耗，但支持其补充的系统运输和机制尚不清楚。在这里，我们证明了急性全身性炎症诱导了粒细胞-巨噬细胞祖细胞和巨噬细胞-树突状祖细胞快速迁移系统的紧急激活，而不是其他祖细胞或干细胞，从骨髓（BM）到局部淋巴毛细血管。祖细胞转运到全身淋巴循环是由Ccl19/Ccr7介导的，不依赖于NF-κB，依赖于Traf6/ i -κB激酶/SNAP23激活，并负责CD205+/CD172a+ 2型常规树突状细胞亚群分泌预先储存的Ccl19和上调骨髓祖细胞Ccr7信号。成熟的髓细胞Traf6信号是抗炎的，是淋巴结髓细胞发育所必需的。本报告揭示了炎症期间髓系祖细胞从骨髓到淋巴的早期直接运输的存在及其机制基础。当身体受到细菌等致病病原体的感染时，免疫系统会激活各种机制来帮助抵抗感染。免疫系统的第一道防线之一是发起炎症反应，帮助清除病原体并招募其他免疫细胞。然而，这种反应可能会过度激活，导致严重的炎症，损害健康的细胞和组织。第二组细胞对抗这种过度炎症，它们与参与早期炎症反应的细胞不同。两种类型的细胞——炎症细胞和抗炎细胞——都是从固定的祖细胞发展而来的，与干细胞不同的是，这些祖细胞已经注定要变成某种类型的细胞。这些固定的祖细胞驻留在骨髓中，然后迅速移动到次级淋巴器官，如淋巴结，在那里它们成熟为功能免疫细胞。在这个过程中，固定的祖细胞从骨髓传递到淋巴管，淋巴管连接着不同的次级淋巴器官，然后扩散到身体的所有组织。然而，目前还不完全清楚这些细胞的确切路线，以及在炎症期间是什么引导它们走向这些淋巴组织。为了研究这一点，Serrano-Lopez， Hegde等人使用了多种技术组合来检测小鼠祖细胞的迁移，这些小鼠被致死剂量的细菌产物引起炎症。这表明，早在感染开始后一到三个小时，祖细胞就已经开始从骨髓向淋巴管移动。Serrano-Lopez、Hegde等人发现，已经存在于次级淋巴器官中的“警报”免疫细胞释放的一种化学物质吸引了这些祖细胞向淋巴组织转移。进一步的实验表明，前往次级淋巴器官的祖细胞已经被细菌产物激活。然后，它们跟随警报免疫细胞释放的化学物质，准备对免疫挑战做出反应，抑制炎症。在患者的炎症淋巴结中也发现了这些固定的祖细胞。这些发现表明，祖细胞的快速循环是一种防御机制，有助于对抗严重的炎症。改变这些细胞从骨髓迁移到次级淋巴器官的方式，可以为炎症和严重感染提供更有效的治疗方法。然而，这些方法需要在实验室和临床试验中进一步测试。
Innate immune cellular effectors are actively consumed during systemic inflammation, but the systemic traffic and the mechanisms that support their replenishment remain unknown. Here, we demonstrate that acute systemic inflammation induces the emergent activation of a previously unrecognized system of rapid migration of granulocyte-macrophage progenitors and committed macrophage-dendritic progenitors, but not other progenitors or stem cells, from bone marrow (BM) to regional lymphatic capillaries. The progenitor traffic to the systemic lymphatic circulation is mediated by Ccl19/Ccr7 and is NF-κB independent, Traf6/IκB-kinase/SNAP23 activation dependent, and is responsible for the secretion of pre-stored Ccl19 by a subpopulation of CD205+/CD172a+ conventional dendritic cells type 2 and upregulation of BM myeloid progenitor Ccr7 signaling. Mature myeloid Traf6 signaling is anti-inflammatory and necessary for lymph node myeloid cell development. This report unveils the existence and the mechanistic basis of a very early direct traffic of myeloid progenitors from BM to lymphatics during inflammation. When the body becomes infected with disease-causing pathogens, such as bacteria, the immune system activates various mechanisms which help to fight off the infection. One of the immune system’s first lines of defense is to launch an inflammatory response that helps remove the pathogen and recruit other immune cells. However, this response can become overactivated, leading to severe inflammatory conditions that damage healthy cells and tissues. A second group of cells counteract this over inflammation and are different to the ones involved in the early inflammatory response. Both types of cells – inflammatory and anti-inflammatory – develop from committed progenitors, which, unlike stem cells, are already destined to become a certain type of cell. These committed progenitors reside in the bone marrow and then rapidly travel to secondary lymphoid organs, such as the lymph nodes, where they mature into functioning immune cells. During this journey, committed progenitors pass from the bone marrow to the lymphatic vessels that connect up the different secondary lymphoid organs, and then spread to all tissues in the body. Yet, it is not fully understood what exact route these cells take and what guides them towards these lymphatic tissues during inflammation. To investigate this, Serrano-Lopez, Hegde et al. used a combination of techniques to examine the migration of progenitor cells in mice that had been treated with lethal doses of a bacterial product that triggers inflammation. This revealed that as early as one to three hours after the onset of infection, progenitor cells were already starting to travel from the bone marrow towards lymphatic vessels. Serrano-Lopez, Hegde et al. found that a chemical released by an “alarm” immune cell already residing in secondary lymphoid organs attracted these progenitor cells towards the lymphatic tissue. Further experiments showed that the progenitor cells travelling to secondary lymphoid organs were already activated by bacterial products. They then follow the chemical released by alarm immune cells ready to respond to the immune challenge and suppress inflammation. These committed progenitors were also found in the inflamed lymph nodes of patients. These findings suggest this rapid circulation of progenitors is a mechanism of defense that contributes to the fight against severe inflammation. Altering how these cells migrate from the bone marrow to secondary lymphoid organs could provide a more effective treatment for inflammatory conditions and severe infections. However, these approaches would need to be tested further in the laboratory and in clinical trials.