Specific targeting of lung ILC2s via NRP1 in pulmonary fibrosis
Specific targeting of lung ILC2s via NRP1 in pulmonary fibrosis
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DOI：
10.1038/s41423-022-00867-0
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发表时间：
2022-04
影响因子：
24.1
通讯作者：
T. Nii;K. Fukushima;H. Kida
中科院分区：
文献类型：
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作者：
T. Nii;K. Fukushima;H. Kida
先天性淋巴样细胞主要是组织驻留免疫细胞，其具有类似于T细胞亚群的多种功能，并且在没有特异性抗原识别的情况下调节组织稳态和先天性免疫。先前的研究已经报道了2型先天淋巴样细胞（ILC 2）在过敏性炎症中的重要作用，例如在哮喘和食物过敏中的那些，并且显示ILC 2在慢性炎症性疾病中起关键作用，包括肺纤维化和自身免疫性疾病[1，2]。组织和疾病特异性先天免疫细胞，包括ILC 2，已被证明在各种其他疾病的发展中是重要的[3-5]。在Nature Immunology上发表的一项研究中，Zhang等人揭示了神经纤毛蛋白-1（NRP 1）是肺ILC 2的特异性标志物，并在纤维化肺中协调ILC 2功能，而不影响其他组织中的ILC 2 [6]。ILC 2定位于全身的各种组织，包括脂肪组织和肺、肠、皮肤、骨髓、脑和肌肉。ILC 2产生2型细胞因子，如白细胞介素（IL）-4，IL-5，IL-9，IL-13和双调蛋白，它们与组织修复，纤维化和先天免疫有关。ILC 2表达胸腺基质淋巴细胞生成素、IL-25和IL-33的受体，这些受体由环境因素（包括屏障表面的感染因子和过敏原）损伤的上皮和血管内皮细胞产生。NRP 1被鉴定为参与心血管系统发育、致病性血管生成、血管通透性和神经系统外器官发生的细胞表面受体。已经鉴定了NRP 1的几种结合伴侣，包括脑信号蛋白3A、血管内皮生长因子-α和转化生长因子（TGF）β1。NRP 1由各种类型的免疫细胞表达;然而，其在ILC 2中的表达在很大程度上是未知的。首先，作者通过挖掘先前报道的scRNA-seq数据，发现小鼠和人类的肺ILC 2在转录组水平高度表达NRP 1 [7，8]。为了比较来自肺、胰腺和大肠和小肠的ILC 2中的NRP 1蛋白表达，通过t分布随机相邻嵌入分析高参数流式细胞术数据集。ILC 2相关标志物的表达模式清楚地区分了来自不同组织的ILC 2，特别是肺ILC 2，其高度表达NRP 1、致瘤性抑制因子2（ST 2）和CC基序趋化因子受体9。这些结果表明ILC 2具有广泛的组织特异性异质性。NRP 1表达在80%的肺ILC 2的表面上检测到，但在来自胰腺或大肠或小肠的ILC 2上或在骨髓中的未成熟ILC 2上未检测到。作者还检查了Rag 1缺失小鼠肺ILC 2中的NRP 1表达，以排除适应性免疫系统的潜在影响。与其他组织相比，Rag 1基因敲除小鼠的肺ILC 2高表达NRP 1。这些数据表明，肺ILC 2中的NRP 1表达不依赖于适应性免疫系统。接下来，为了确定NRP 1表达是否依赖于来自肺组织微环境的信号，作者检查了个体发育期间不同小鼠组织ILC 2上的NRP 1表达，并与来自肺或肠的单核免疫细胞进行了共培养实验。NRP 1的表达逐渐增加，在肺ILC 2的整个个体发育和表达在80%的ILC 2从成年小鼠。在体外共培养系统中发现，NRP 1在肺ILC 2s表面的表达被肠单核免疫细胞抑制，而NRP 1在肺ILC 2s表面的表达被肠单核免疫细胞抑制。
Innate lymphoid cells are predominantly tissue-resident immune cells that have diverse functions similar to T-cell subsets and regulate tissue homeostasis and innate immunity without specific antigen recognition. Previous studies have reported the important roles of type 2 innate lymphoid cells (ILC2s) in allergic inflammation, such as those in asthma and food allergies, and shown that ILC2s play key roles in chronic inflammatory diseases, including pulmonary fibrosis and autoimmune disease [1, 2]. Tissue-and disease-specific innate immune cells, including ILC2s, have been shown to be important in the development of various other diseases [3–5]. In a study published in Nature Immunology, Zhang et al. revealed that neuropilin-1 (NRP1) is a specific marker for lung ILC2s and coordinates ILC2 functions in fibrotic lungs without affecting ILC2s in other tissues [6]. ILC2s localize to various tissues throughout the body, including adipose tissue and the lungs, intestines, skin, bone marrow, brain, and muscles. ILC2s produce type 2 cytokines, such as interleukin (IL)-4, IL-5, IL-9, IL-13, and amphiregulin, which are related to tissue repair, fibrosis, and innate immunity. ILC2s express receptors for thymic stromal lymphopoietin, IL-25, and IL-33, which are produced by epithelial and vascular endothelial cells damaged by environmental factors, including infectious agents and allergens at barrier surfaces. NRP1 was identified as a cell-surface receptor involved in the development of the cardiovascular system, pathogenic angiogenesis, vascular permeability, and organogenesis outside the nervous system. Several binding partners of NRP1 have been identified, including semaphorin 3A, vascular endothelial growth factor-α, and transforming growth factor (TGF) β1. NRP1 is expressed by various types of immune cells; however, its expression in ILC2s is largely uncharacterized. First, the authors found that lung ILC2s in both mice and humans highly expressed NRP1 at the transcriptomic level by mining previously reported scRNA-seq data [7, 8]. To compare NRP1 protein expression among ILC2s from the lungs, pancreas, and large and small intestines, high-parameter flow cytometry datasets were analyzed by t-distributed stochastic neighbor embedding. The expression patterns of ILC2-related markers clearly differentiated ILC2s from different tissues, especially lung ILC2s, which highly expressed NRP1, suppressor of tumorigenicity 2 (ST2), and CC motif chemokine receptor 9. These results suggest that ILC2s have extensive tissue-specific heterogeneity. NRP1 expression was detected on the surface of 80% of lung ILC2s but not on ILC2s from the pancreas or large or small intestine or on immature ILC2s in the bone marrow. The authors also examinedNRP1 expression in lung ILC2s from Rag1-null mice to exclude potential influence by the adaptive immune system. Lung ILC2s from Rag1-null mice highly expressed NRP1 compared with those from other tissues. These data demonstrate that NRP1 expression in lung ILC2s is independent of the adaptive immune system. Next, to determine whether NRP1 expression is dependent on signals from the lung tissue microenvironment, the authors examined NRP1 expression on ILC2s from different mouse tissues during ontogeny and performed coculture experiments with mononuclear immune cells derived from the lungs or intestines. NRP1 expression gradually increased in lung ILC2s throughout ontogeny and was expressed in 80% of ILC2s from adult mice. In vitro coculture systems revealed that NRP1 expression on the surface of lung ILC2s was suppressed by intestinal mononuclear immune cells, whereas NRP1 …