MicroRNAs Modulate The Non-canonical NF-κB Pathway By Regulating Ikkα Expression During The Monocyte/macrophage Differentiation

Monocytes are a type of the nongranular leukocytes, which supply peripheral tissues with macrophages and dendritic cells (DC) precursors and constitute an important part of the innate immune system. It has been more and more uncovered by emerging publications that deregulation of macrophage functions and differentiation is often involved in many types of diseases including cancer. However, the molecular events happened during monocyte-macrophage differentiation are still largely unknown. Any further knowledge about this important process will definitely give more in sight to understand the differentiation of monocytes and will provide more therapeutic opportunity to treat cancer and other major related diseases.MicroRNAs became the focus of many researchers since it has been discovered at 1993. Emerging evidence suggested that microRNAs are important component of immune cell differentiation and function.In this study with human primary monocytes and macrophages, we show that during monocyte-macrophage differentiation, microRNAs, miR-223, miR-15a and miR-16 play a crucial role in regulating macrophage function by modulating non-canonical NF-κB signaling pathway. We found that during the differentiation of macrophage, these microRNAs are dramatically decreased. Bioinformatics analysis suggested that the IκB protein kinase, IKKαis the sharing target of these three microRNAs. We demonstrated that the levels of these microRNAs determine the expression amounts of IKKαin monocyte and macrophages respectively. Importantly, the high IKKαexpression in junction with NIK stabilization leads to an increased level of p52. Due to the absence of RelB expression in untreated macrophages, the high level of p52 represses target genes of the non-canonical NF-κB pathway. However, this inhibitory effect will be turned to promotional effect when the cells were further challenged by LPS. Thus, our data suggested during the differentiation of macrophage, the changes of certain microRNAs likely prevent macrophage hyperactive and yet prime the macrophage for a robust response to proinflammatory stimuli.