Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease

Abstract

BackgroundThe IL23/Th17 pathway is essential for the onset of inflammatory bowel disease (IBD), yet the specific mechanism by which this pathway initiates the disease remains unknown. In this study, we identify the mechanisms that mediate cross-talk between the IL23 pathway and the intestinal barrier in IBD.ResultsThe downstream targets of the IL23 pathway were identified by RNA array profiling and confirmed by immunohistochemical staining. The role of miRNAs that interact with IL23 was explored in mice with TNBS-induced colitis. Claudin-8 (CLDN8), a multigene family protein that constitutes the backbone of tight junctions, was identified as a novel target of IL23 in IBD. CLDN8 was significantly downregulated in IBD patients with inflamed colonic mucosa, and in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice. Therapeutic treatment of colitis in mice using an IL23 antibody restored CLDN8 abundance, in parallel with recovery from colitis. In addition, we identify miR-223 as a novel mediator of the crosstalk between the IL23 signal pathway and CLDN8 in the development of IBD. MiR-223 was upregulated in IBD, and its activity was regulated through the IL23 pathway. Antagomir inhibition of miR-223 reactivated CLDN8 and improved a number of signs associated with TNBS-induced colitis in mice.ConclusionsOur study characterizes a new mechanistic pathway in IBD, in which miR-223 interacts with the IL23 pathway by targeting CLDN8. Strategies designed to disrupt this interaction may provide novel therapeutic agents for the management of IBD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0901-8) contains supplementary material, which is available to authorized users.

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms

“…Indeed, TNFα, IFNγ, interleukins (IL) 1 IL6, IL9, and IL23 have been found to decrease claudin expression and increase epithelial permeability in vitro and in vivo [10, 57, 69-73]. These cytokines interact with their enterocyte receptors and induce intracellular signaling cascades resulting in the altered activity of various transcriptional factors in the nucleus.…”

“…Evidence suggest that induction of different miRs can be responsible for the decreased expression of intestinal epithelial claudins during mucosal inflammation. Specifically, miR-29 suppresses claudin-1 level [78], miR-93 inhibits claudin-3 [71], and miR-223 downregulates claudin-8 expression [73]. Of note, claudins are not the only targets for different miRs at epithelial junctions, since this mechanism was also implicated in the expressional regulation of occludin and ZO-1 [79, 80].…”

Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3

“…9, 10, 11 Of note, recent studies suggest that miRNAs regulate ER stress and induce apoptosis. 12, 13 For example, miR-15b-5p repressed UPR signaling by suppressing Rab1A and accelerated apoptosis in human hepatocellular carcinoma.…”

MicroRNAs in intestinal barrier function, inflammatory bowel disease and related cancers — their effects and therapeutic potentials

“…By contrast, miR-31 expression increased while miR-21 , miR-155 and miR-146a levels decreased in colonic CD3 + T cells in UC remission [18]. Table 1 presents microRNAs with validated target transcripts in gut mucosa or cells of the immune system in the context of IBD or in different mouse models [16,19,20 • ,21 •• ,22–32]. …”