ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.
ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.
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DOI：
10.7554/elife.10066
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发表时间：
2016-01-18
期刊：
影响因子：
7.7
通讯作者：
Powrie F
中科院分区：
文献类型：
--
作者：
Pearson C;Thornton EE;McKenzie B;Schaupp AL;Huskens N;Griseri T;West N;Tung S;Seddon BP;Uhlig HH;Powrie F
先天性淋巴样细胞（ILC）有助于宿主防御和组织修复，但可诱导免疫病理学。最近的工作揭示了ILC的组织特异性作用;然而，一个小群体如何对免疫稳态产生巨大影响的问题仍然不清楚。我们确定了ILC 3在肠道组织中发挥作用的两种机制。ILC驱动的结肠炎依赖于粒细胞巨噬细胞集落刺激因子（GM-CSF）的产生，该因子招募并维持肠道炎性单核细胞。存在于肠中的ILC也以高度动态的过程进入和离开密码锁。在结肠炎期间，ILC 3从隐睾斑块中动员，这是一个可以通过阻断GM-CSF来抑制的过程，并且动员先于组织中其他地方的炎性病灶。这些数据一起鉴定了ILC 3内的IL-23 R/GM-CSF轴作为肠中先天效应细胞积累和肠炎症反应中ILC时空动力学的关键控制点。http://dx.doi.org/10.7554/eLife.10066.001克罗恩病和溃疡性结肠炎是人体自身免疫系统引起大肠炎症的疾病。这些自身免疫性疾病可能会严重衰弱，难以治疗。然而，对肠道炎症因素的进一步了解可能会导致新的有效治疗方法。免疫细胞称为先天性淋巴样细胞是最近发现的，并迅速显示在宿主防御，组织修复和炎症调节中发挥作用。现在已知有几组先天性淋巴样细胞;每组的特征是控制细胞发育的基因和细胞释放的小蛋白（称为细胞因子）。一组先天淋巴样细胞，ILC 3，通常在肠道中发现，尽管数量很少。鉴于已知先天淋巴细胞管理炎症反应，ILC 3可能有助于肠道炎症。然而，目前尚不清楚如此少量的细胞如何能如此显著地使肠道发炎。Pearson等人现在揭示了这些先天淋巴细胞用于放大炎症反应和加剧肠道炎症的两种机制。首先，在小鼠和人类中，ILC 3被发现是一种名为GM-CSF的细胞因子的关键来源，该细胞因子招募额外的免疫细胞，进一步促进肠道炎症。其次，虽然ILC 3传统上被认为是固定的免疫细胞，但Pearson等人发现，这些细胞可以在肠组织内移动，如果它们被激活，则可以从该组织内的起始点移动。这两种机制可以解释ILC 3如何触发整个肠道发生的炎症。这些实验表明，阻断GM-CSF细胞因子的产生或改变ILC 3的运动或活性可能有助于减少肠道炎症。然而，使用GM-CSF阻断药物来预防结肠炎和类似疾病可能存在问题，因为GM-CSF在肠道中也起着重要的保护作用。尽管如此，临床试验正在进行中，以研究使用抗GM-CSF药物治疗其他炎症性疾病（如类风湿性关节炎）。这些研究可以深入了解这些药物是否也能缓解患有肠道炎症的试验参与者。DOI：http://dx.doi.org/10.7554/eLife.10066.002网站
Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response. DOI: http://dx.doi.org/10.7554/eLife.10066.001 Crohn’s disease and ulcerative colitis are diseases in which the body’s own immune system causes inflammation of the large intestine. These autoimmune diseases can be severely debilitating and difficult to treat. However an improved understanding of the factors that contribute to the intestinal inflammation may lead to new and effective treatments. Immune cells called innate lymphoid cells were discovered recently, and shown quickly to play a role in host defense, tissue repair and inflammation regulation. Several groups of innate lymphoid cells are now known; each group is characterized by the genes that control the cell’s development and the small proteins (called cytokines) that the cells release. One group of innate lymphoid cells, the ILC3s, are generally found in the intestinal tract, albeit in small numbers. Given that innate lymphoid cells are known to manage inflammatory responses, it is possible that ILC3s contribute to intestinal inflammation. However, it remains unclear how such a small population of cells could so dramatically inflame the gut. Pearson et al. now reveal two mechanisms that these innate lymphoid cells use to amplify the inflammatory response and exacerbate intestinal inflammation. First, in both mice and humans, ILC3s were found to be a key source of a cytokine called GM-CSF, which recruits additional immune cells that further promote intestinal inflammation. Secondly, while ILC3s were traditionally regarded as immobile immune cells, Pearson et al. discovered that these cells can move within the intestinal tissue and mobilize from their starting points within this tissue if they are activated. These two mechanisms could explain how ILC3s can trigger inflammation that occurs throughout the gut. The experiments suggest that blocking production of the GM-CSF cytokine or altering ILC3 movement or activity may help reduce intestinal inflammation. However, the use of GM-CSF blocking drugs to protect against colitis and similar conditions could be problematic, because GM-CSF also plays an important protective role in the intestines. Nevertheless, clinical trials are underway to investigate the use of anti-GM-CSF drugs to treat other inflammatory conditions (such as rheumatoid arthritis). These studies could offer insight into whether these drugs provide relief to trial participants who suffer from intestinal inflammation as well. DOI: http://dx.doi.org/10.7554/eLife.10066.002