Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals

By F. Bazzoni, M. Rossato, M. Fabbri, D. Gaudiosi, M. Mirolo, L. Mori, NICOLA TAMASSIA, A. Mantovani, M. Cassatella, M. Locati. Proceedings of the National Academy of Sciences of the United States of America, 2009

606 citations recorded by the source corpus.

Inflammation involves a coordinated, sequential, and self limiting sequence of events controlled by positive and negative regulatory mechanisms. Recent studies have shown that microRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide noncoding RNAs, contribute to the regulation of inflammation by repressing gene expression at the posttranscriptional level. In this study, we characterize the profile of miRNAs induced by LPS in human polymorphonuclear neutrophils (PMN) and monocytes. In particular, we identify miR-9 as the only miRNA (among 365 analyzed) up-regulated in both cell types after TLR4 activation. miR-9 is also induced by TLR2 and TLR7/8 agonists and by the proinflammatory cytokines TNF-α and IL-1β, but not by IFNγ. Among the 3 different genes encoding miR-9 precursors in humans, we show that LPS selectively induces the transcription of miR-9–1 located in the CROC4 locus, in a MyD88- and NF-κB-dependent manner. In PMN and monocytes, LPS regulates NFKB1 at both the transcriptional and posttranscriptional levels, and a conserved miR-9 seed sustained a miR-9-dependent inhibition of the NFKB1 transcript. Overall, these data suggest that TLR4-activated NF-κB rapidly increases the expression of miR-9 that operates a feedback control of the NF-κB-dependent responses by fine tuning the expression of a key member of the NF-κB family.

Subfields: Cancer Research

View Paper: https://www.semanticscholar.org/paper/d6606a81da0678ecbae7bba9064e9ca75be5aa26

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Citations in the corpus

microRNAs and the immune response (2009, background): “Studies into the mechanism of LPS-induced miR9, miR-146a and miR-155 expression demonstrate a central role of the pro-inflammatory transcription factor nuclear factor (NF)-kB [8 ,11,13].”
MicroRNAs: the fine-tuners of Toll-like receptor signalling (2011, background): “More recently, the TLR-responsive miRNA miR-9 was shown to directly target NFKB1 mRN”
miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice (2011, background): “We identified three miRNA genes (miR-146a, miR-132, and miR-155) whose expression is sharply upregulated in response to LPS, and this list was later expanded further to include miR-9, miR-21, and miR-147 through the work of others (Bazzoni et al., 2009; Liu et al., 2009; Sheedy et al., 2010).”
Neutrophils in the activation and regulation of innate and adaptive immunity (2011, background): “More recent evidence highlights that de novo induction of microRNAs might be part of the crucial regulatory circuits that control neutrophil gene expressio”
Neutrophils, from marrow to microbes. (2010, background): “MiR-9 is induced in LPS and TNF-a-stimulated neutrophils by NF-kB and exerts a feedback inhibition on NF-kB translation (Bazzoni et al., 2009).”
Macrophage plasticity and polarization: in vivo veritas. (2012, neutral): “miRNAs have emerged as regulators of phagocyte activation and function (34, 139), but their role in macrophage polarization needs to be further defined.”
Neutrophil-Derived Cytokines: Facts Beyond Expression (2014, background): “For instance, miR9 was for the first time demonstrated to inhibit NFKB1/p50 transcripts in human neutrophils exposed to pro-inflammatory signals, operating in this manner as a feedback control for NFKB1/p50dependent responses (29).”
The complexity of NF-κB signaling in inflammation and cancer (2013, background): “Several miRNAs have been shown to be transcriptional targets of NF-κB including miR-9, miR-21, miR-143, miR-146 and miR-224 [145-150].”