MiR-142 Is Required for Staphylococcus aureus Clearance at Skin Wound Sites via Small GTPase-Mediated Regulation of the Neutrophil Actin Cytoskeleton
MiR-142 Is Required for Staphylococcus aureus Clearance at Skin Wound Sites via Small GTPase-Mediated Regulation of the Neutrophil Actin Cytoskeleton
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DOI：
10.1016/j.jid.2016.11.018
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发表时间：
2017-04-01
影响因子：
6.5
通讯作者：
Mori, Ryoichi
中科院分区：
文献类型：
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作者：
Tanaka, Katsuya;Kim, Sang Eun;Mori, Ryoichi
microRNAs（miRNAs）是一类小的非编码RNA，通过与互补的靶mRNA结合来调节蛋白质的翻译。我们之前鉴定了miR-142家族的两个成熟成员，miR-142- 5 p和miR-142- 3 p，作为炎症相关的miRNA，在伤口愈合中具有潜在的作用。在这里，我们证明了这两种miRNAs在伤口浸润的中性粒细胞和巨噬细胞中显著表达，并在伤口愈合中发挥核心作用。我们使用可交换基因捕获方法产生miR-142（-/-）小鼠，并显示与野生型小鼠相比，miR-142（-/-）小鼠中金黄色葡萄球菌感染的皮肤伤口的愈合显著延迟。MiR-142（-/-）小鼠在S.金黄色葡萄球菌感染的皮肤伤口部位，也更容易受到伤口感染的水平传播。MiR-142（-/-）中性粒细胞表现出由于趋化行为而改变的吞噬作用，包括增强的F-肌动蛋白组装、扰乱的细胞极性和增加的细胞运动性。我们发现这些变化与细胞骨架调节有关，并且在miR-142（-/-）中性粒细胞中小GTP酶的表达显著增加。总的来说，我们的数据表明miR-142家族对于保护免受S.金黄色葡萄球菌感染及其在伤口部位的清除。miR-142- 3 p和miR-1425 p通过控制伤口部位中性粒细胞中的小GT3翻译在肌动蛋白细胞骨架调节中发挥非冗余作用。
MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein translation by binding to complementary target mRNAs. We previously identified two mature members of the miR-142 family, miR-142-5p and miR-142-3p, as inflammation-related miRNAs with potential roles in wound healing. Here, we demonstrated that these two miRNAs are prominently expressed in wound-infiltrated neutrophils and macrophages and play central roles in wound healing. We generated miR-142(-/-) mice using the exchangeable gene-trap method and showed that healing of Staphylococcus aureus-infected skin wounds was significantly delayed in miR142(-/-) mice compared with that in wild-type mice. MiR-142(-/-) mice exhibited abnormal abscess formation at S. aureus-infected skin wound sites and were also more susceptible to horizontal transmission of wound infections. MiR-142(-/-) neutrophils showed altered phagocytosis as a consequence of chemotactic behavior, including enhanced F-actin assembly, disturbed cell polarity, and increased cell motility. We showed that these changes were linked to cytoskeletal regulation, and that expression of the small GTPases was markedly increased in miR-142(-/-) neutrophils. Collectively, our data demonstrate that the miR-142 family is indispensable for protection against S. aureus infection and its clearance at wound sites. MiR-142-3p and miR-1425p play nonredundant roles in actin cytoskeleton regulation by controlling small GTPase translation in neutrophils at wound sites.