Neutrophils are rapidly recruited from the peripheral blood to the inflammatory site to initiate inflammatory response against pathogenic infections. The process to recruit neutrophils must be properly regulated since the abnormal accumulation of neutrophils can cause organ damage and dysfunction. The acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a common cause of respiratory failure that is characterized by the infiltration of neutrophils and epithelial integrity disruption. Indeed, recent studies suggest a pathogenic role of neutrophils in the clinic severity of the coronavirus disease 2019 (COVID-19) ARDS. The chemokine CXCL1, which is rapidly induced by inflammatory stimuli, plays a key role in neutrophil influx during lung inflammation. The molecular basis of Cxcl1 induction is not fully understood. Here we report that TET1, a member of the ten eleven translocation (TET) methylcytosine dioxygenase protein family, displays a striking specificity in the regulation of gene expression in macrophages. RNA sequencing (RNA-seq) analysis showed that Tet1 disruption significantly altered the expression of only 48 genes that include Cxcl1 and several other genes known to be important for cell migration and trafficking in bone marrow derived macrophages (BMDMs) in response to LPS stimulation. TET1 regulates the induction of Cxcl1 by facilitating the DNA demethylation of the Cxcl1 promoter. In Tet1-/- mice, the induction of Cxcl1 was suppressed, resulting in defective neutrophil recruitment to the lung during LPS-induced acute lung injury. Our results identify a novel epigenetic mechanism that selectively controls Cxcl1 induction and neutrophil recruitment during acute lung injury.

中文翻译：

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TET1 通过 DNA 去甲基化控制 Cxcl1 诱导并促进急性肺损伤期间的中性粒细胞募集

中性粒细胞从外周血迅速募集到炎症部位，以启动针对病原体感染的炎症反应。必须适当调节募集中性粒细胞的过程，因为中性粒细胞的异常积累会导致器官损伤和功能障碍。急性呼吸窘迫综合征 (ARDS)/急性肺损伤 (ALI) 是呼吸衰竭的常见原因，其特征是中性粒细胞浸润和上皮完整性破坏。事实上，最近的研究表明，中性粒细胞在 2019 年冠状病毒病（COVID-19）ARDS 的临床严重程度中具有致病作用。由炎症刺激迅速诱导的趋化因子 CXCL1 在肺部炎症期间的中性粒细胞流入中起关键作用。Cxcl1 诱导的分子基础尚不完全清楚。在这里我们报告TET1，十一个11 易位(TET) 甲基胞嘧啶双加氧酶蛋白家族的成员，在巨噬细胞基因表达的调控中显示出惊人的特异性。RNA 测序 (RNA-seq) 分析表明，Tet1 破坏仅显着改变了 48 个基因的表达，其中包括 Cxcl1 和其他几个已知对响应 LPS 刺激的骨髓来源巨噬细胞 (BMDM) 的细胞迁移和运输很重要的基因。TET1 通过促进 Cxcl1 启动子的 DNA 去甲基化来调节 Cxcl1 的诱导。在 Tet1-/- 小鼠中，Cxcl1 的诱导被抑制，导致在 LPS 诱导的急性肺损伤期间有缺陷的中性粒细胞募集到肺中。