Epithelium-Intrinsic MicroRNAs Contribute to Mucosal Immune Homeostasis by Promoting M-Cell Maturation

Abstract

M cells in the follicle-associated epithelium (FAE) of Peyer’s patches (PPs) serve as a main portal for external antigens and function as a sentinel in mucosal immune responses. The scarcity of these cells has hampered identification of M cell-specific molecules. Recent efforts have begun to provide insight into antigen transcytosis and differentiation of M cells; however, the molecular mechanisms underlying these processes are not fully elucidated. Small non-coding RNAs including microRNA (miRNA) have been reported to regulate gene expression and control various biological processes such as cellular differentiation and function. To evaluate the expression of miRNAs in FAE, including M cells, we previously performed microarray analysis comparing intestinal villous epithelium (VE) and PP FAE. Here we confirmed FAE specific miRNA expression levels by quantitative PCR. To gain insight into miRNA function, we generated mice with intestinal epithelial cell-specific deletion of Dicer1 (DicerΔIEC) and analyzed intestinal phenotypes, including M-cell differentiation, morphology and function. DicerΔIEC mice had a marked decrease in M cells compared to control floxed Dicer mice, suggesting an essential role of miRNAs in maturation of these cells. Furthermore, transmission electron microscopic analysis revealed that depletion of miRNA caused the loss of endosomal structures in M cells. In addition, antigen uptake by M cells was impaired in DicerΔIEC mice. These results suggest that miRNAs play a significant role in M cell differentiation and help secure mucosal immune homeostasis.

Post-Transcriptional Regulation of Toll-Interacting Protein in the Intestinal Epithelium

“…miRNAs in IECs play a role in cellular differentiation, e.g. M-cells[ 61 ] and goblet cells, helminth infection[ 62 ], flora composition[ 63 ], lipid metabolism, and inflammatory response[ 40 ]. miR-31 is coded on chromosome 4 near the region with the ifn α/β genes; however, ifn α/β genes are not transcribed constitutively in S-IECs or in L-IECs[ 64 ], suggesting a specific transcriptional activation of miR-31 expression in S-IECs.…”

Exosome‐mediated effects and applications in inflammatory bowel disease

“…Dicer knockout in IECs of mice led to decreased goblet cell numbers, increased cryptic apoptosis, and inhibited intestinal barrier function, implying an important role of IEC miRNAs in supporting epithelial constitution and protection (McKenna et al, 2010). Functionally, IEC miRNAs contribute to the morphology and function of M cells, a crucial component of the mucosal antigen-sampling system (Nakato et al, 2016). Chen et al (2016) Detected six miRNAs that were significantly upregulated in IPEC-J2 cells alongside other molecules like proliferating cell nuclear antigen (PCNA), caudal type homeobox 2 (CDX2), and insulin-like growth factor 1 receptor (IGF-1R), after treatment with milk-derived exosomes.…”

“…Studies in this field continue to show promising results. Some such studies have identified exosomes in the placenta as early biomarkers of preeclampsia , exosomal microRNAs and circulating exosomes as biomarkers of gastrointestinal cancer (Nedaeinia et al, 2017), and circulating exosomes as biomarkers of cardiovascular diseases (Parizadeh et al, 2019). Other conditions in which exosomes have been identified as potential biomarkers include diabetes type 1 (Garcia-Contreras et al, 2017), breast cancer (Jia et al, 2017) and prostate cancer (Duijvesz et al, 2011) among others.…”

Biomarkers and therapeutic targets: microRNA roles in the pathophysiology, diagnosis and management of eosinophilic esophagitis

“…For example, miR-34a and miR-365 have roles in the maturation of gut-associated lymphoid tissue (GALT). miR-34a has been shown to downregulate members of the Notch1 signaling pathway that control normal differentiation of M cells, a highly specialized epithelial cell [30] . In this way, repression of Notch-1 signaling by miR-34a leads to normal development of structures at the mucosal interface that sample antigen and initiate immune responses.…”