Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury.
Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury.
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DOI：
10.1096/fj.202002407r
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Yuan X
中科院分区：
文献类型：
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作者：
Berg NK;Li J;Kim B;Mills T;Pei G;Zhao Z;Li X;Zhang X;Ruan W;Eltzschig HK;Yuan X
脓毒症和脓毒症相关的肺部炎症显著导致危重病的发病率和死亡率。在这里，我们研究了神经元引导蛋白可以在内毒素诱导的肺损伤期间协调炎症事件的假设。通过靶向阵列，我们将netrin-1鉴定为脂多糖（LPS）处理的巨噬细胞中上调最多的神经元引导蛋白。此外，我们发现netrin-1在浸润的骨髓细胞中高度富集，特别是在LPS诱导的肺损伤期间的巨噬细胞中。转录研究表明，缺氧诱导因子HIF-1α在LPS处理期间参与netrin-1的转录诱导。随后，髓样区室中netrin-1的缺失（Ntn 1 loxp/loxp LysM Cre）导致了夸大的死亡率和肺部炎症。令人惊讶的是，进一步的研究显示，Ntn 1 loxp/loxp LysM Cre小鼠中自然杀伤细胞（NK细胞）浸润增强，NK细胞趋化因子（C-C基序）配体2（CCL 2）的中和逆转了夸大的肺部炎症。总之，这些研究提供了对髓样细胞衍生的netrin-1通过调节NK细胞的CCL 2依赖性浸润来控制肺部炎症的功能性见解。
Sepsis and sepsis‐associated lung inflammation significantly contribute to the morbidity and mortality of critical illness. Here, we examined the hypothesis that neuronal guidance proteins could orchestrate inflammatory events during endotoxin‐induced lung injury. Through a targeted array, we identified netrin‐1 as the top upregulated neuronal guidance protein in macrophages treated with lipopolysaccharide (LPS). Furthermore, we found that netrin‐1 is highly enriched in infiltrating myeloid cells, particularly in macrophages during LPS‐induced lung injury. Transcriptional studies implicate hypoxia‐inducible factor HIF‐1α in the transcriptional induction of netrin‐1 during LPS treatment. Subsequently, the deletion of netrin‐1 in the myeloid compartment (Ntn1loxp/loxp LysM Cre) resulted in exaggerated mortality and lung inflammation. Surprisingly, further studies revealed enhanced natural killer cells (NK cells) infiltration in Ntn1loxp/loxp LysM Cre mice, and neutralization of NK cell chemoattractant chemokine (C‐C motif) ligand 2 (CCL2) reversed the exaggerated lung inflammation. Together, these studies provide functional insight into myeloid cell‐derived netrin‐1 in controlling lung inflammation through the modulation of CCL2‐dependent infiltration of NK cells.