IL-1β and the Intestinal Epithelial Tight Junction Barrier

The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn’s disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1β (IL-1β), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1β-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1β-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1β on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1β modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.

Mechanosensitive calcium signaling promotes epithelial tight junction remodeling by activating RhoA

Epithelia maintain an effective barrier by remodeling cell-cell junctions in response to mechanical stimuli. Cells often respond to mechanical stress through activating RhoA and remodeling actomyosin. Previously, we found that local leaks in the barrier are rapidly repaired by localized, transient activation of RhoA – ″Rho flares″ – but how Rho flares are initiated remains unknown. Here, we discovered that intracellular calcium flashes occur in Xenopus laevis epithelial cells undergoing Rho flare-mediated remodeling of tight junctions. Calcium flashes originate at the site of barrier leaks and propagate into the cell. Depletion of intracellular calcium or inhibition of mechanosensitive calcium channels (MSC) reduced the amplitude of calcium flashes and diminished the activation of Rho flares. Furthermore, MSC-dependent calcium influx was necessary to maintain global barrier function by regulating local repair of tight junctions through efficient junction contraction. We propose that MSC-dependent calcium flashes are an important mechanism allowing epithelial cells to sense and respond to local leaks induced by mechanical stimuli.

Exploring Effects of Chitosan Oligosaccharides on the DSS-Induced Intestinal Barrier Impairment In Vitro and In Vivo

Intestinal barrier dysfunction is an essential pathological change in inflammatory bowel disease (IBD). The mucus layer and the intestinal epithelial tight junction act together to maintain barrier integrity. Studies showed that chitosan oligosaccharide (COS) had a positive effect on gut health, effectively protecting the intestinal barrier in IBD. However, these studies usually focused on its impact on the intestinal epithelial tight junction. The influence of COS on the intestinal mucus layer is still poorly understood. In this study, we explored the effect of COS on intestinal mucus in vitro using human colonic mucus-secreted HT-29 cells. COS relieved DSS (dextran sulfate sodium)-induced mucus defects. Additionally, the structural characteristics of COS greatly influenced this activity. Finally, we evaluated the protective effect of COS on intestinal barrier function in mice with DSS-induced colitis. The results indicated that COS could manipulate intestinal mucus production, which likely contributed to its intestinal protective effects.

Epithelial paraphagy is a luminal lipophilic signal sensor and promotes transepithelial cholesterol clearance

Epithelial endocytosis is essential for physiological homeostasis. The current dogma is that all endocytotic mechanisms involve only single-membrane vesicles at the plasma membrane. Here, we report a previously undescribed LC3-associated phagocytosis mechanism which forms double-membrane phagosomes from the epithelial tight-junction paracellular membranes, which we term “paraphagy”. We observed that paraphagy is present in epithelia of the renal, respiratory, circulatory, and male reproductive systems. In the epididymis, paraphagy takes up lipophilic cargo, including apolipoproteins, by involving the surface low-affinity IgG-receptor Fcgr2b and occludin-bound intracellular HDL-receptor ATP5b. In this way, extracellular lipophilic signals are sensed and intracellular phagolysosomes are maintained. Occludin-null male mice show arrested paraphagy and impaired phagolysosome in proximal epididymal compartments, accompanying cholesterol accumulation, ApoJ deposition and dysregulated metabolic-dependent processes in distal compartments, including redox-promoted VK-dependent MGP-carboxylation. We propose that paraphagy senses and distinguishes the luminal lipophilic signals in epithelia and modulates their function via crosstalk across physiological compartments.