Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells

Abstract

Background: Mast cells (MCs) have been found to play a critical role during development of inflammatory bowel disease (IBD) that characterized by dysregulation of inflammation and impaired intestinal barrier function. However, the function of MCs in IBD remains to be fully elucidated. Results: In our study, we used exosomes isolated from human mast cells-1 (HMCs-1) to culture with NCM460, HT-29 or CaCO2 of intestinal epithelial cells (IECs) to investigate the communication between MCs and IECs. We found that MCs-derived exosomes significantly increased intestinal epithelial permeability and destroyed intestinal barrier function, which is attributed to exosome-mediated functional miRNAs were transferred from HMCs-1 into IECs, leading to inhibit tight junction-related proteins expression, including tight junction proteins 1 (TJP1, ZO-1), Occludin (OCLN), Claudin 8 (CLDN8). Microarray and bioinformatic analysis have further revealed that a panel of miRNAs target different tight junction-related proteins. Interestingly, miR-223 is enriched in mast cell-derived exosome, which inhibit CLDN8 expression in IECs, while treatment with miR-223 inhibitor in HT-29 cells significantly reversed the inhibitory effect of HMCs-1-derived exosomes on CLDN 8 expression. Most importantly, enrichment of MCs accumulation in intestinal mucosa of patients with IBD compared with those healthy control. Conclusions: These results indicated that enrichment of exosomal miR-223 from HMCs-1 inhibited CLDN8 expression, leading to destroy intestinal barrier function. These finding provided a novel insight of MCs as a new target for therapeutic treatment of IBD.

Exosome-based immunotherapy: a promising approach for cancer treatment

“…Mast cells (MCs) can secrete exosomes that display biological functions in RNA and protein transfer, intercellular communication and immunoregulation [127,128]. It was pointed that MC-exosomes have been reported to destroy intestinal barrier function, which is attributed to exosome-carried miRNAs transferred to targeted cells [129]. Recent studies found that MC-derived exosomes can be taken up by lung cancer cells, and subsequently increase cancer cell proliferation by transferring KIT protein [130].…”

Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

“…Mast cells play a critical role in development of IBD. A recent study showed that exosomes from human mast cells are loaded with miR-223, and that delivery of this miRNA into IECs downregulates the expression of the TJ-related proteins ZO-1, occludin, and claudin-8, which in turn elicit the subsequent increase in intestinal permeability that contributes to inflammation and disease development [ 73 ].…”

miR‐223 improves intestinal inflammation through inhibiting the IL‐6/STAT3 signaling pathway in dextran sodium sulfate‐induced experimental colitis

“…It has been reported that miR‐223 is involved in the pathogenesis of IBD by regulating various immune cells and signaling pathways 4‐8 . Furthermore, miR‐223 from human mast cells‐1 (HMCs‐1) inhibits CLDN8 expression to destroy intestinal barrier function in IBD 19 …”