JAK-STAT Pathway Regulation of Intestinal Permeability: Pathogenic Roles and Therapeutic Opportunities in Inflammatory Bowel Disease

Abstract

The epithelial barrier forms the interface between luminal microbes and the host immune system and is the first site of exposure to many of the environmental factors that trigger disease activity in chronic inflammatory bowel disease (IBD). Disruption of the epithelial barrier, in the form of increased intestinal permeability, is a feature of IBD and other inflammatory diseases, including celiac disease and type 1 diabetes. Variants in genes that regulate or belong to the JAK-STAT signaling pathway are associated with IBD risk. Inhibitors of the JAK-STAT pathway are now effective therapeutic options in IBD. This review will discuss emerging evidence that JAK inhibitors can be used to improve defects in intestinal permeability and how this plays a key role in resolving intestinal inflammation.

IL-22-Activated MUC13 Impacts on Colonic Barrier Function through JAK1/STAT3, SNAI1/ZEB1 and ROCK2/MAPK Signaling

“…This is the first study providing evidence on how aberrant MUC13 expression affects intestinal epithelial barrier function upon IL-22 activation (summarized in Figure 9). In our study, we showed that the absence of MUC13 altered the gene expression of several tight junctions as main regulators of paracellular permeability [27][28][29][30][31]. Particularly, a significant upregulation of CLDN1, CLDN3 and CLDN4 was noted in MUC13 siRNA transfected IECs whereas a significant alteration in mRNA expression was also shown for CLDN1, CLDN4, CLDN7 and TJP2 upon IL-22 activation.…”

“…Subsequently, JAK1, MAPK1, MAPK9, ROCK2, SNAI1 and ZEB1 were, based on their changing mRNA expression pattern due to MUC13 knockdown (Figure 1D) and for their role in epithelial barrier homeostasis [4,[27][28][29], further studied as potential downstream regulators of MUC13-mediated barrier dysfunction (Figures 2C,D and 4). MUC13 deficiency induced an elevated expression of MAPK1, ROCK2, SNAI1 and ZEB1 mRNA upon IL-22 stimulation, whereas simultaneous MUC1 and MUC13 knockdown abolished these effects (Figure 4A,E,G,I).…”

“…Although these qPCR results failed to recapitulate the effect of MUC13 knockdown initially observed in our transcriptome dataset, these results further indicate a potential role for MUC13 in the modulation of the expression/activity of these key barrier regulators, which also seems to be partially mediated through MUC1 signaling. Subsequently, JAK1, MAPK1, MAPK9, ROCK2, SNAI1 and ZEB1 were, based on their changing mRNA expression pattern due to MUC13 knockdown (Figure 1D) and fo their role in epithelial barrier homeostasis [4,[27][28][29], further studied as potential down stream regulators of MUC13-mediated barrier dysfunction (Figures 2C,D and 4). MUC1 deficiency induced an elevated expression of MAPK1, ROCK2, SNAI1 and ZEB1 mRNA upon IL-22 stimulation, whereas simultaneous MUC1 and MUC13 knockdown abolished these effects (Figure 4A,E,G,I).…”

Ocular instillation of conditioned medium from mesenchymal stem cells is effective for dry eye syndrome by improving corneal barrier function

“…3a and Table 1). Moreover, these signalling pathways are related to in ammation and barrier function in various tissues [32,33,34,35]. We found that inhibition of these signalling pathways suppressed in ammation and barrier dysfunction of hCECs, especially inhibition of the TGF-β pathway, contributing signi cantly to in ammation, showing effects similar to those of hAdMSC-CM (Supplementary Fig.…”

Probiotics and gut microbiota: mechanistic insights into gut immune homeostasis through TLR pathway regulation

“…138 Altered permeability enhances the translocation of pro-inflammatory stimuli into the lamina propria (LP), triggering inflammatory cytokine-mediated changes to the tight junctions that have been associated with IBD susceptibility. 139 TJs are not static barriers but highly dynamic structures that are constantly being remodelled due to external stimuli, such as food components and the microbiome. TJ is composed of over 50 proteins that help in the maintenance of epithelial integrity.…”