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Group 2 Innate Lymphoid Cells Must Partner with the Myeloid–Macrophage Lineage for Long-Term Postviral Lung Disease
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-07-08 , DOI: 10.4049/jimmunol.2000181
Kangyun Wu 1 , Xinyu Wang 1 , Shamus P Keeler 1 , Benjamin J Gerovac 1 , Eugene V Agapov 1 , Derek E Byers 1 , Susan Gilfillan 2 , Marco Colonna 2 , Yong Zhang 1 , Michael J Holtzman 3, 4
Affiliation  

Key Points ILC2s are activated even after injury from respiratory viral infection is resolved. ILC2s contribute to a chronic type 2 immune response after viral infection. ILC2s depend on myeloid–macrophage lineage cells to drive postviral disease. Visual Abstract Group 2 innate lymphoid cells (ILC2s) are implicated in host defense and inflammatory disease, but these potential functional roles need more precise definition, particularly using advanced technologies to better target ILC2s and engaging experimental models that better manifest both acute infection and chronic, even lifelong, disease. In this study, we use a mouse model that applies an improved genetic definition of ILC2s via IL-7r–conditional Rora gene targeting and takes advantage of a distinct progression from acute illness to chronic disease, based on a persistent type 2 immune response to respiratory infection with a natural pathogen (Sendai virus). We first show that ILC2s are activated but are not required to handle acute illness after respiratory viral infection. In contrast, we find that this type of infection also activates ILC2s chronically for IL-13 production and consequent asthma-like disease traits that peak and last long after active viral infection is cleared. However, to manifest this type of disease, the Csf1-dependent myeloid–macrophage lineage is also active at two levels: first, at a downstream level, this lineage provides lung tissue macrophages (interstitial macrophages and tissue monocytes) that represent a major site of Il13 gene expression in the diseased lung; and second, at an upstream level, this same lineage is required for Il33 gene induction that is necessary to activate ILC2s for participation in disease at all, including IL-13 production. Together, these findings provide a revised scheme for understanding and controlling the innate immune response leading to long-term postviral lung diseases with features of asthma and related progressive conditions.

中文翻译:

第 2 组先天淋巴样细胞必须与髓细胞-巨噬细胞谱系合作才能治疗长期病毒后肺病

关键点即使在呼吸道病毒感染造成的损伤得到解决后,ILC2s 仍会被激活。ILC2 有助于病毒感染后的慢性 2 型免疫反应。ILC2s 依赖髓系-巨噬细胞谱系细胞来驱动病毒后疾病。Visual Abstract 第 2 组先天淋巴细胞 (ILC2s) 与宿主防御和炎症疾病有关,但这些潜在的功能作用需要更精确的定义,特别是使用先进技术来更好地靶向 ILC2s 并使用能够更好地表现急性感染和慢性感染的实验模型,甚至终生,疾病。在这项研究中,我们使用一种小鼠模型,该模型通过 IL-7r 条件性 Rora 基因靶向应用改进的 ILC2 遗传定义,并利用从急性疾病到慢性疾病的明显进展,基于对自然病原体(仙台病毒)呼吸道感染的持续 2 型免疫反应。我们首先表明 ILC2s 被激活但不需要处理呼吸道病毒感染后的急性疾病。相比之下,我们发现这种类型的感染也会长期激活 ILC2s 以产生 IL-13 和随后的哮喘样疾病特征,这些特征在活动性病毒感染被清除后达到峰值并持续很长时间。然而,为了表现这种类型的疾病,Csf1 依赖性髓样巨噬细胞谱系也在两个水平上活跃:首先,在下游水平,该谱系提供肺组织巨噬细胞(间质巨噬细胞和组织单核细胞),它们代表了肺组织的主要部位。 Il13 基因在患病肺中的表达;其次,在上游层面,Il33 基因诱导需要相同的谱系,这是激活 ILC2 参与疾病所必需的,包括 IL-13 产生。总之,这些发现为理解和控制导致具有哮喘和相关进展性疾病特征的长期病毒后肺部疾病的先天免疫反应提供了修订方案。
更新日期:2020-07-08
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