Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a+CD103+ dendritic cells (DCs), pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103+ DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, two day-old C57BL/6J, CD103+ DC-deficient Batf3^-/- or Clec9a^gfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared to wild type mice, hyperoxia-exposed Batf3^-/- mice showed reduced levels of IL-12p40, IFN-γ and TNF-α, fewer IFN-γ-producing CD4+ T cells and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9a^gfp-/-mice. Further, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A+ cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103+ DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103+ DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.

中文翻译：

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新生儿高氧诱导的鼻病毒感染炎症反应需要肺 CD103+ 树突状细胞和 Clec9a 信号传导

早产儿，尤其是那些患有支气管肺发育不良 (BPD) 的婴儿，会反复出现严重的呼吸道病毒性疾病。我们已经表明，未成熟小鼠（一种 BPD 模型）的高氧暴露会增加产生肺 IL-12 的 Clec9a+CD103+ 树突状细胞 (DC)、鼻病毒 (RV) 感染后的促炎反应和气道高反应性。然而，对于 RV 诱导的炎症反应，CD103+ DCs 和 Clec9a（一种结合坏死细胞细胞骨架丝状肌动蛋白 (F-actin) 的 DAMP 受体）的需求尚未得到证实。为了测试这一点，两天大的 C57BL/6J、CD103+ DC 缺陷型 Batf3 ^-/-或 Clec9a ^gfp-/-小鼠暴露于常氧或高氧14天。此外，用针对 CD103 的中和抗体处理选定的小鼠。高氧后立即给小鼠鼻内接种RV。我们发现，与野生型小鼠相比，暴露于高氧的 Batf3 ^-/-小鼠的 IL-12p40、IFN-γ 和 TNF-α 水平降低，产生 IFN-γ 的 CD4+ T 细胞减少，RV 感染后气道反应性降低。在抗 CD103 处理和 Clec9a ^{gfp-/-中观察到类似的效果}老鼠。此外，高氧增加了气道死细胞数量和细胞外 F-肌动蛋白水平。最后，对患有呼吸窘迫综合征的早产儿的研究表明，气管抽吸物中 CLEC9A 的表达与 IL12B 的表达呈正相关，这与 CLEC9A+ 细胞在人类和小鼠中负责 IL-12 产生的观点一致。我们得出结论，高氧诱导的对 RV 感染的促炎反应需要 CD103+ DCs 和 Clec9a。在早产儿中，Clec9a 介导的 CD103+ DC 激活可能会促进对病毒感染的促炎反应，从而导致呼吸系统疾病的发生。