Monocytes serve as danger sensors within the circulation. The activation of blood-borne monocytes by inflammatory stimuli triggers their adhesion and homing to sites of tissue injury, where they differentiate into macrophages and collectively aid in the resolution of damage. However, the chronic accumulation of macrophages at these sites of injury is a hallmark of inflammatory diseases such as rheumatoid arthritis, Crohn’s disease and atherosclerosis.
Dynamic changes in gene expression are associated with monocyte to macrophage differentiation, where PU.1, Signal Transducer and Activator of Transcription (STATs) and CCAAT/Enhancer Binding Protein (C/EBP)s are key transcription factors that drive this alteration in cellular phenotype and function.
Importantly, numerous studies have identified critical roles for both microRNAs (miRNAs) and RNA-binding proteins (RBPs) in posttranscriptionally regulating monocyte and macrophage biology. However, the posttranscriptional regulation of monocyte to macrophage differentiation has generally been limited to studies detailing miRNA-based targeting of individual transcription factors or effector molecules that either stimulate or delay this phenotypic conversion.
In contrast to miRNAs, RBPs mediate both quantitative and qualitative changes to the transcriptome, interacting with pre-mRNAs to influence (alternative) splicing, transcript stability, editing, subcellular localization and translational activation or repression. This broad arsenal of RNA-based control points enables RBPs to modulate the proteome in response to immunogenic stimuli, shifting inflammatory cells from an immature or naive state to a mature or activated state, as has previously been established in lymphoid cells.
In recent times, authors discovered that expression of the RBP Quaking (QKI) is induced in human restenotic lesion-resident vascular smooth muscle cells (VSMCs), where it directly mediates a splicing event in the Myocardin pre-mRNA that governs VSMC function. This finding prompted the authors to investigate whether QKI could similarly serve as an inflammation-sensitive posttranscriptional guide during monocyte to macrophage differentiation.
Here they show that the RBP QKI plays a critical role in regulating the conversion of monocytes into macrophages in, for example, atherosclerotic lesions. Depletion of QKI protein impairs monocyte adhesion, migration, differentiation into macrophages and foam cell formation in vitro and in vivo. RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal striking changes in QKI-dependent messenger RNA levels and splicing of RNA transcripts.
These studies pinpoint QKI as a dynamic regulator of pre-mRNA splicing and expression profiles that drive monocyte activation, adhesion and differentiation into macrophages, and facilitates their conversion into foam cells.
http://www.nature.com/ncomms/2016/160331/ncomms10846/full/ncomms10846.html
Regulating monocyte differentiation and atherosclerosis development
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