Table_2_Early-life hyperoxia-induced Flt3L drives neonatal lung dendritic cell expansion and proinflammatory responses.xlsx

Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103+ DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11bhi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11bhi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects.

罹患慢性肺部疾病——支气管肺发育不良（bronchopulmonary dysplasia, BPD）的早产儿，在呼吸道病毒感染后会出现复发性咳嗽与喘息症状。目前，此类慢性呼吸道症状的致病机制仍未明确。我们的研究证实，作为BPD模型的新生小鼠经高氧暴露后，其肺脏内的CD103+树突状细胞（CD103+ DCs）会被激活，且这类树突状细胞是鼻病毒（RV）感染引发过度炎症反应的必要介导因素。鉴于CD103+ DCs对特异性抗病毒应答至关重要，且其发育依赖于生长因子Flt3配体（Flt3L），我们提出如下假说：早期生命阶段的高氧暴露会刺激Flt3L的表达，进而促进肺脏CD103+ DCs的扩增与活化，最终介导炎症反应。本研究发现，高氧暴露不仅在数量上增加了新生小鼠肺脏CD103+ DCs与CD11bhi DCs的占比，还诱导了这两类细胞的促炎转录特征；同时，高氧暴露可上调Flt3L的表达水平。抗Flt3L抗体可在常氧与高氧环境下阻断CD103+ DCs的发育；尽管该抗体未对CD11bhi DCs的基础数量产生影响，但可中和高氧暴露对这类细胞的调控作用。此外，抗Flt3L抗体还可抑制高氧暴露诱导的鼻病毒感染促炎应答。对出生第一周内因呼吸窘迫接受机械通气的早产儿的气管抽吸物进行检测后发现，后续发展为BPD的患儿，其体内FLT3L、白细胞介素12p40（IL-12p40）、白细胞介素12p70（IL-12p70）与γ干扰素（IFN-γ）的水平显著更高，且FLT3L的水平与促炎细胞因子的水平呈正相关。本研究揭示了早期生命阶段高氧暴露对肺脏树突状细胞发育与功能的致敏作用，以及Flt3L在介导上述效应中的关键贡献。