Insulin-like Growth Factor 1 Supports a Pulmonary Niche that Promotes Type 3 Innate Lymphoid Cell Development in Newborn Lungs.,Immunity

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Insulin-like Growth Factor 1 Supports a Pulmonary Niche that Promotes Type 3 Innate Lymphoid Cell Development in Newborn Lungs.
Immunity ( IF 25.5 ) Pub Date : 2020-02-18 , DOI: 10.1016/j.immuni.2020.01.005
Katherine Oherle ₁ , Elizabeth Acker ₁ , Madeline Bonfield ₂ , Timothy Wang ₃ , Jerilyn Gray ₁ , Ian Lang ₁ , James Bridges ₄ , Ian Lewkowich ₅ , Yan Xu ₄ , Shawn Ahlfeld ₃ , William Zacharias ₆ , Theresa Alenghat ₇ , Hitesh Deshmukh ₈

Affiliation

Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

Type 3 innate lymphoid cells (ILC3s) are critical for lung defense against bacterial pneumonia in the neonatal period, but the signals that guide pulmonary ILC3 development remain unclear. Here, we demonstrated that pulmonary ILC3s descended from ILC precursors that populated a niche defined by fibroblasts in the developing lung. Alveolar fibroblasts produced insulin-like growth factor 1 (IGF1), which instructed expansion and maturation of pulmonary ILC precursors. Conditional ablation of IGF1 in alveolar fibroblasts or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Premature infants with bronchopulmonary dysplasia, characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced IGF1 concentrations and pulmonary ILC3 numbers. These findings indicate that the newborn period is a critical window in pulmonary immunity development, and disrupted lung development in prematurely born infants may have enduring effects on host resistance to respiratory infections.

中文翻译：

胰岛素样生长因子 1 支持肺部生态位，促进新生儿肺部 3 型先天淋巴细胞发育。

3 型先天淋巴细胞 (ILC3) 对于新生儿期肺部防御细菌性肺炎至关重要，但指导肺部 ILC3 发育的信号仍不清楚。在这里，我们证明了肺部 ILC3 起源于 ILC 前体，这些前体占据了由发育中的肺部成纤维细胞定义的生态位。肺泡成纤维细胞产生胰岛素样生长因子 1 (IGF1)，指示肺 ILC 前体细胞的扩张和成熟。有条件地去除肺泡成纤维细胞中的 IGF1 或从 ILC 前体中删除 IGF-1 受体会中断 ILC3 的生物合成，并使新生小鼠易患肺炎。患有支气管肺发育不良的早产儿，其特征是出生后肺泡发育中断和呼吸道感染发病率增加，其 IGF1 浓度和肺部 ILC3 数量降低。这些发现表明，新生儿期是肺部免疫发育的关键窗口，早产儿肺部发育中断可能会对宿主对呼吸道感染的抵抗力产生持久影响。

更新日期：2020-02-20

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