The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.

中文翻译：

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N-乙酰半胱氨酸抑制细菌脂肽介导的中性粒细胞通过发育中的大脑脉络丛的迁移。

与早产和其他围产期并发症相关的神经系统疾病的病因学通常涉及感染性或促炎性成分。抗氧化剂分子的使用已被证明有助于保护新生儿的大脑免受伤害。脉络丛-CSF系统在成年阶段塑造了中枢神经系统对炎症的反应，但是在发育过程中脉络膜血液-CSF屏障发生的神经免疫相互作用尚鲜为人知。我们之前曾描述过，向新生小鼠外周给药TLR2配体PAM3CSK4（P3C）（一种原型革兰氏阳性细菌脂肽）会诱导先天免疫细胞向CSF迁移。在这里，我们发现在暴露于P3C的新生大鼠中，嗜中性粒细胞通过脉络丛的迁移进入脑脊液，服用抗氧化剂N-乙酰半胱氨酸后，其被取消。结合脉络丛的光片显微镜成像，血液CSF屏障的差异化模型和多重细胞因子检测，我们显示脉络膜上皮细胞通过特定的细胞因子分泌模式对细菌侵害作出反应，从而导致嗜中性白细胞的选择性积累并在脉络丛中转运到脑脊液。N-乙酰半胱氨酸通过阻止嗜中性粒细胞迁移穿过脉络膜基质血管的内皮和形成血脑脊液屏障的上皮而起作用，而不会干扰嗜中性粒细胞的血细胞计数，脉络丛的嗜中性粒细胞嗜性和脉络膜趋化因子驱动的趋化性。N-乙酰半胱氨酸减轻了缺氧缺血对P3C致敏新生大鼠的伤害。总体，数据显示，内皮和上皮双重检查点控制嗜中性粒细胞跨脉络膜迁移至发育中的大脑。他们还指出了N-乙酰半胱氨酸通过以前未曾描述的机制降低了炎症相关的围产期损伤的有害作用的功效，即在不干扰对感染的全身性炎症反应的情况下，抑制了天然免疫细胞跨脉络丛的迁移。