MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway
MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway
复制标题
MiR-127 调节巨噬细胞极化并促进肺部炎症和损伤。
DOI：
10.4049/jimmunol.1402088
复制
发表时间：
2015-02-01
影响因子：
4.4
通讯作者：
Shi, Liyun
中科院分区：
文献类型：
--
作者：
Ying, Hangjie;Kang, Yanhua;Shi, Liyun
极化巨噬细胞反应被认为在多种免疫病理生理学中具有关键作用。然而，巨噬细胞功能形成的分子机制在很大程度上仍然未知。在这项研究中，我们揭示了miR-127在巨噬细胞发育中的关键作用，从而揭示了炎症和肺损伤的发病机制。特别是，miR-127被证明在TLR接合时被显著诱导，并被M2-倾向性细胞因子抑制。miR-127在巨噬细胞中的增强表达导致促炎细胞因子的产生显著增加，而miR-127的缺失损害M1基因表达并导致M2偏向性反应。因此，肺内施用miR-127导致了夸大的肺部炎症和损伤。相反，拮抗miR-127抑制了促炎细胞因子的产生，并使小鼠对炎症相关病理学更难治。从机制上讲，miR-127表现出靶向B细胞淋巴瘤6（Bcl 6），并显著下调其表达，随后下调双特异性磷酸酶1（Dusp 1），这反过来又增强了JNK激酶的激活，从而促进了促炎性巨噬细胞的发育。因此，用Bcl 6或Dusp 1的表达或JNK活性的抑制进行的重建损害了miR-127介导的M1促炎性巨噬细胞的偏斜，而Bcl 6或Dusp 1表达的干扰废除了抗miR-127的抗炎特性。总之，这些数据确立了miR-127作为巨噬细胞发育过程中的分子开关以及治疗炎症性疾病的潜在靶点。
A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127-mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti-miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases.