Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE

Abstract

Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR-124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-α. Further studies showed that miR-124 could directly target the 3′-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-α production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation.

Long noncoding RNA nuclear enriched abundant transcript 1/miRNA-124 axis correlates with increased disease risk, elevated inflammation, deteriorative disease condition, and predicts decreased survival of sepsis

“…MiRNAs are evolutionarily conserved noncoding RNA oligonucleotides that regulate the expression of numerous gene targets, and a variety of studies have indicated that miRNAs play crucial roles in mechanisms of human inflammatory diseases. [22–25] For miR-124, some in vivo or in vitro experiments disclose that it may facilitate the suppression of inflammatory responses in sepsis. [14,15,26] For instance, a study discovers that miR-124 downregulation attenuates the PPARγ-mediated inhibition of pro-inflammatory cytokines in RAW264.7 cells.…”

Dietary vinegar prevents kidney stone recurrence via epigenetic regulations

“…The IF assays were performed as previously described [14]. The kidney sections were incubated with xylol and descending concentrations of ethanol.…”

Anti-Inflammatory MicroRNAs and Their Potential for Inflammatory Diseases Treatment

“…Its downregulation has also been reported in RA patients ( 73 ). The expression of miR-124 is significantly reduced in intestinal macrophages in pediatric intestinal failure patients in contrast to overexpression when miR-124 inhibits intestinal inflammation through attenuating production of IL-6 and TNF-α via targeting STAT3, a major factor in inflammatory response, and acetylcholinesterase, a negatively regulator of the cholinergic anti-inflammatory signal ( 74 ). Sun et al reported that miR-124 targets STAT3 to decrease IL-6 production and TNF-α converting enzyme believed to reduce TNF-α release in response to LPS ( 75 ).…”