Abstract
MicroRNAs are universal post-transcriptional regulators in genomes. They have the ability of buffering gene expressional programs, contributing to robustness of biological systems and playing important roles in development, physiology and diseases. Here, we identified a microRNA, miR-125a, as a positive regulator of granulopoiesis. MiR125a knockout mice show reduced infiltration of neutrophils in the lung and alleviated tissue destruction after endotoxin challenge as a consequence of decreased neutrophil numbers. Furthermore, we demonstrated that this significant reduction of neutrophils was due to impaired development of granulocyte precursors to mature neutrophils in an intrinsic manner. We showed that Socs3, a critical repressor for granulopoiesis, was a target of miR-125a. Overall, our study revealed a new microRNA regulating granulocyte development and supported a model in which miR-125a acted as a fine-tuner of granulopoiesis.
Highlights
Neutrophils, known as polymorphonuclear leukocytes (PMNs), are the most abundant granulocytes which play a crucial role in immune defense and inflammatory reaction
We developed engineering MiR125a knockout mice to study the function of miR-125a in vivo
We identified MiR125a knockout mice had decreased neutrophil numbers and reduced infiltration of neutrophils in the lung in LPS shock model
Summary
Neutrophils, known as polymorphonuclear leukocytes (PMNs), are the most abundant granulocytes which play a crucial role in immune defense and inflammatory reaction. The receptor of G-CSF is mainly expressed in granulocytic progenitor cells and mature neutrophils [6].The binding of G-CSF to its receptor triggers receptor dimerization and tyrosine phosphorylation of JAK1, JAK2 and TYK2, which belong to the Janus family of protein tyrosine kinases (JAKs) [7]. These phosphorylate residues in the cytosolic part of the G-CSF receptor and subsequently activate mitogen-activated protein (MAP) kinase like ERK pathway [8] and the signal transducers and activators of transcription (STATs) including STAT1 and STAT3 (4, 10). Mice with Socs conditionally knocked out in hematopoietic cells [10, 11] develop neutrophilia and inflammatory pathologies
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