Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome
Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome
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DOI：
10.1164/rccm.201410-1782oc
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发表时间：
2016-02-15
影响因子：
24.7
通讯作者：
Ingram, Rebecca J.
中科院分区：
文献类型：
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作者：
Muir, Roshell;Osbourn, Megan;Ingram, Rebecca J.
原理：IL-17 A旨在通过增强中性粒细胞募集来帮助驱动急性呼吸窘迫综合征（ARDS）的早期发病机制。虽然IL-17 A是T辅助细胞17的典型细胞因子，但它是由大量淋巴细胞产生的，在ARDS时其来源尚不清楚。目的：明确IL-17 A的细胞来源及其在肺损伤早期的作用。用雾化LPS（100 μ g）或铜绿假单胞菌感染在野生型（C57 BL/6）和IL-17敲除（KO）小鼠中诱导肺损伤。通过流式细胞术对小鼠肺中表达ROR γ t（IL-17产生的转录调节因子）的细胞进行了详细的表型分析。测量和主要结果：与野生型小鼠相比，IL-17 A KO小鼠的肺中观察到中性粒细胞浸润减少了100倍。小鼠肺中的大多数ROR γ t（+）细胞是最近鉴定的第3组先天淋巴样细胞（ILC 3）。详细表征揭示这些肺ILC 3（pILC 3）与肠中描述的那些是离散的。这些细胞的关键作用通过在重组酶激活基因2 KO小鼠中诱导损伤来验证，这些小鼠缺乏T细胞，但保留了先天淋巴细胞。重组酶激活基因2 KO小鼠的病理学没有观察到改善。结论：IL-17在肺损伤期间迅速产生，并在早期免疫发病机制中发挥重要作用。这主要是由不同的pILC 3群体协调的。pILC 3活性的调节可能增强对ARDS中所见的炎症失调的早期控制，从而开辟新的治疗靶点。
Rationale: IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Although IL-17A is the archetypal cytokine of T-helper 17 cells, it is produced by a number of lymphocytes, the source during ARDS being unknown.Objectives: To identify the cellular source and the role of IL-17A in the early phase of lung injury.Methods: Lung injury was induced in wild-type (C57BL/6) and IL-17 knockout (KO) mice with aerosolized LPS (100 mu g) or Pseudomonas aeruginosa infection. Detailed phenotyping of the cells expressing ROR gamma t, the transcriptional regulator of IL-17 production, in the mouse lung at 24 hours was performed by flow cytometry.Measurements and Main Results: A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared with wild-type mice. The majority of ROR gamma t(+) cells in the mouse lung were the recently identified group 3 innate lymphoid cells (ILC3s). Detailed characterization revealed these pulmonary ILC3s (pILC3s) to be discrete from those described in the gut. The critical role of these cells was verified by inducing injury in recombinase-activating gene 2 KO mice, which lack T cells but retain innate lymphoid cells. No amelioration of pathology was observed in the recombinase-activating gene 2 KO mice.Conclusions: IL-17 is rapidly produced during lung injury and significantly contributes to early immunopathogenesis. This is orchestrated largely by a distinct population of pILC3s. Modulation of the activity of pILC3s may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets.