The significance of long non-coding RNAs in the pathogenesis, diagnosis and treatment of inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBD) are a group of chronic relapsing gastrointestinal inflammatory diseases with significant global incidence. Although the pathomechanism of IBD has been extensively investigated, several aspects of its pathogenesis remain unclear. Long non-coding RNAs (lncRNAs) are transcripts with more than 200 nucleotides in length that have potential protein-coding functions. LncRNAs play important roles in biological processes such as epigenetic modification, transcriptional regulation and post-transcriptional regulation. In this review, we summarize recent advances in research on IBD-related lncRNAs from the perspective of the overall intestinal microenvironment, as well as their potential roles as immune regulators, diagnostic biomarkers and therapeutic targets or agents for IBD.

Keywords: diagnostic biomarker; immune regulator; inflammatory bowel diseases; intestinal barrier; intestinal microenvironment; lncRNAs; therapeutic target.

Figure 1.

Structure of intestinal barriers. Intestinal homeostasis of a healthy body depends on four barriers. Beneficial bacteria in gut microbiota form an important microbial protective barrier against pathogens. Biochemical barriers include mucus, antimicrobial peptides, tissue repair factors, secretory IgA, and bacterial metabolites, all of which can inhibit the proliferation, adhesion and invasion of pathogenic bacteria. Physical barriers constitute intact intestinal mucosal epithelium, tight junctions, adhesive junctions and desmosomes between epithelial cells, which can effectively block bacteria, viruses and endotoxins. The immunological barrier is mainly composed of GALT and diffuse immune cells, which can recognize antigens in the intestinal environment, activate innate and adaptive immunity, resist invasion by pathogenic microorganisms, and suppress immune responses when necessary.

Figure 2.

Mechanisms of lncRNA function. (A) As signals, lncRNAs directly interact with transcriptional factors to indicate gene regulation. (B) As decoys, lncRNAs can titrate away transcription factors away from chromatin, blocking effects of transcriptional factors. (C) lncRNAs act as decoys for miRNA target site, titrating miRNAs away from their mRNA targets and indicating mRNA expression. (D) As guides, lncRNAs can recruit chromatin modifying enzymes to target genes, either in cis or in trans to distant target genes. (E) As scaffolds, lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes. (F) For post-transcriptional regulation, lncRNAs directly modulate processing of their mRNA targets at multiple levels, including translation, splicing and degradation. (G) For protein coding, eIF4E recognizes sORF on lncRNA to recruit ribosomes and initiate translation.

Figure 3.

Intestinal commensal bacteria target lncRNAs to regulate immune responses and affect intestinal homeostasis. LncRNA ENO1-IT1 and IRF5 can form competing endogenous RNA (ceRNA) networks and crosstalks occur through shared miR-22–3p. LncRNA HIF1A-AS2 can target transcriptional regulators (NF-κB) to regulate related molecular signaling pathways.

Figure 4.

LncRNAs regulate mucosal biochemical and physical barriers. (A) LncRNAs directly target mRNA and regulate their splicing, editing, subcellular distribution and stability. (B) LncRNAs and mRNAs can form competing endogenous RNA (ceRNA) networks in which crosstalks occur through shared miRNA response elements. (C) LncRNAs act as precursors of miRNA and scaffolds of RBPs and miRNAs.

Figure 5.

LncRNAs regulate epithelial cell proliferation and apoptosis. (A) LncRNAs regulate the expression of downstream target genes through sponge miRNA, and then activate the NF-κB pathway, promoting inflammation and apoptosis. (B) LncRNAs directly target mRNAs to regulate gene expression, activating the NF-κB pathway and promoting inflammation and apoptosis. (C) LncRNAs act as modular scaffolds for RNA binding proteins, coordinating their localization and specific binding to the target genes, inducing cell apoptosis and inflammation. (D) LncRNA NEAT1 regulates glucose metabolism via miR-410–3p/LDHA axis, influencing intestinal barrier homeostasis. (E) LncRNA LINC01272 promotes TGF-β1-induced epithelial-mesenchymal transition (EMT) by targeting miR-153–5p, leading to loss of epithelial cells and increase in tissue damage.

Figure 6.

LncRNAs regulate immune responses and epithelial restitution. (A) LncRNAs affect the transformation of BMDCs into immune tolerant phenotypes. (B) LncRNA regulate Th cell differentiation to balance the production of inflammatory cytokines. (C) LncRNAs are involved in neutrophil infiltration to promote IBD occurrence and development. (D) LncRNAs participate in regulation of autophagy to regulate intestinal homeostasis. (E) LncRNAs promote cell proliferation to sustain the maintenance and functions of ILC3s. (F) LncRNAs participate in exosome-mediated polarization of macrophages.