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.

Highlights

  • Pediatric intestinal failure (IF) is a devastating condition that can be defined as the inability to maintain sufficient nutrient, fluid, electrolyte and micronutrient, causing unsustain adequate growth in children.[1]

  • We showed TNF-α and IL-6 co-localized in CD68-positive cells, indicating the intestinal macrophages are the major source of IL-6 and TNF-α released in patients (Figures 1f and g)

  • The expression p-signal transducer and activator of transcription 3 (STAT3) and AChE increased in intestinal macrophages of pediatric intestinal failure patients

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Summary

Introduction

Pediatric intestinal failure (IF) is a devastating condition that can be defined as the inability to maintain sufficient nutrient, fluid, electrolyte and micronutrient, causing unsustain adequate growth in children.[1]. We predicted that miR-124 can attenuate intestinal macrophages activation by targeting both STAT3 and AChE

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