Neudecker et al. define a role for a microRNA, miR-223, in regulating the inflammatory tone of the intestine by constraining nlrp3 inflammasome activation in CCR2+ monocytes and attenuating excessive IL-1β–driven inflammation. Therapeutic nanoparticle delivery of miR-223 mimetics limits experimental colitis.

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Barrier dysfunction has been implicated in the pathophysiology of eosinophilic esophagitis (EoE). TGF-β1, a potent pleiotropic molecule, is increased in EoE, however, no study has evaluated its influence on esophageal epithelial barrier. We hypothesized that TGF-β1 regulates barrier dysfunction in EoE. We aimed to determine the role of TGF-β1 in epithelial barrier in models of EoE. To examine the impact of TGF-β1 on esophageal barrier, immortalized human esophageal epithelial (EPC2-hTERT) cells were exposed to TGF-β1 during the 3-dimensional air liquid interface (3D-ALI) model in vitro. TGF-β1 exposure diminished EPC2-hTERT barrier function as measured by transepithelial electrical resistance (TEER) and 3kDa FITC dextran paracellular flux (FITC Flux) and H&E assessment revealed prominent cellular separation. In analysis of epithelial barrier molecules, TGF-β1 led to the specific reduction in expression of the tight-junction molecule, claudin-7 and this was prevented by TGF-β receptor I inhibitor. shRNA mediated claudin-7 knockdown diminished epithelial barrier function, while claudin-7 overexpression resulted in protection from TGF-β1-mediated barrier dysfunction. In analysis of pediatric EoE biopsies claudin-7 expression was decreased, altered localization was observed by immunofluorescence analysis and the TGF-β1 downstream transcription factor phosphorylated SMAD2/3 (pSMAD2/3) was increased. Our data suggest that TGF-β1 participates in esophageal epithelial barrier dysfunction through claudin-7 dysregulation.

Background Fibrostenosis and stricture are well-recognized endpoints in Crohn’s disease (CD). We hypothesized that stricturing-CD is characterized by eosinophilia and epithelial-IL-33. We proposed that eosinophil exposure to IL-33 would perpetuate inflammatory chronicity and subsequent fibrostenosis. Methods We performed a retrospective study of 74 children with inflammatory and stricturing ileal-CD comparing clinicopathological features to immunohistochemical measures of eosinophilia and IL-33. To scrutinize eosinophil patterns we developed a novel eosinophil-peroxidase (EPX)-score encompassing number, distribution and degranulation. Human eosinophils and intestinal fibroblasts were cultured with IL-33 and IL-13 and inflammatory and remodeling parameters were assessed. Anti-eosinophil therapy was also administered to the Crohn’s-like ileitis model (SAMP1/SkuSlc). Results Our novel EPX-score was more sensitive than H&E-staining, revealing significant differences in eosinophil patterns, comparing inflammatory and stricturing pediatric CD. A significant relationship between ileal-eosinophilia and complicated clinical/histopathological phenotype including fibrosis was determined. IL-33 induced significant eosinophil EPX-secretion and IL-13 production. Exposure to eosinophils in the presence of IL-33, ‘primed’ fibroblasts to increase pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), eosinophil-associated chemokines (CCL24, CCL26) and IL-13Rα2 production. Production of fibrogenic molecules (collagen 1A2, fibronectin and periostin) increased following exposure of ‘primed’-fibroblasts to IL-13. Epithelial-IL-33 was increased in pediatric Crohn’s-ileitis and strongly associated with clinical and histopathological activity, ileal eosinophilia and complicated, fibrostenotic disease. SAMP1/SkuSlc eosinophil-targeted treatment resulted in significant improvements in inflammation and remodeling. Conclusions Our study of specimens from pediatric patients with ileal CD linked eosinophil patterns and IL-33 to fibrosis; and suggested these may contribute to the perpetuation of inflammation and subsequent stricture in pediatric CD.