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.
Macrophage polarization is critical for dictating host defense against pathogens and injurious agents. Dysregulation of macrophage differentiation has been implicated in infectious and inflammatory diseases. Here, we show that protein kinase B/Akt1 signaling induced by Staphylococcus aureus is essential in shifting macrophages from an antimicrobial phenotype (M1) to a functionally inert signature. Akt1(-/-)mice consistently had enhanced bacterial clearance and greater survival, compared with their wild-type littermates. The blunted M1 macrophage reaction driven by Akt1 was associated with decreased RelA/nuclear factor κB activity. Furthermore, by repression of the expression of suppressor of cytokine signaling 1 (SOCS1), microRNA 155 revealed to promote the transcription of M1 signature genes in macrophages from Akt1(-/-) mice. Accordingly, blocking of microRNA 155 in macrophages from Akt1(-/-)mice or knockdown of SOCS1 in cells from wild-type mice disabled or enabled, respectively, an M1 macrophage shift and antibacterial response. These results thus establish an Akt1-mediated, microRNA-involved circuit that regulates pathogen-driven macrophage polarization and, subsequently, the host response to infection.
Background: LXR inhibits the development of atherosclerosis. It remains unknown whether LXR regulates IL-5 expression, an atheroprotective cytokine, in macrophages. Results: LXR induces macrophage IL-5 expression in an LXRE-dependent manner. It also induces IL-5 expression in aortic root area of LDLR Ϫ/Ϫ mice.
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