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MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 194(3)
- Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Transcription, Genetic
MAP Kinase Signaling System
Immunology
Acute Lung Injury
Macrophage polarization
Inflammation
Lung injury
Biology
Ligands
Proinflammatory cytokine
Cell Line
Pathogenesis
Mice
RNA interference
Sepsis
Dual-specificity phosphatase
medicine
Immunology and Allergy
Animals
Regulation of gene expression
Gene Expression Profiling
Macrophages
Toll-Like Receptors
Dual Specificity Phosphatase 1
Pneumonia
Macrophage Activation
Cell biology
DNA-Binding Proteins
Endotoxins
Disease Models, Animal
MicroRNAs
Gene Expression Regulation
biology.protein
Proto-Oncogene Proteins c-bcl-6
RNA Interference
Disease Susceptibility
medicine.symptom
Transcriptome
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 194
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....e5b705e9fc29dd0199e7aa6576facaf4