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P021. Subepithelial eosinophils expressing muscarinic receptors and corticotropin-releasing factor disrupt mucosal barrier in inactive ulcerative colitis

C. Wallon1, M. Persborn1, M. Jönsson1, A. Ericson1, M. Carlson2, D.M. McKay3, J.D. Söderholm1

1Linköping University, Linköping, Sweden; 2Uppsala University, Uppsala, Sweden; 3University of Calgary, Calgary, AB, Canada

Aim: Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) by genetic, functional and epidemiological (stress-related) evidence. We previously showed the importance of mast cells and corticotropin-releasing factor (CRF) in regulating mucosal barrier in human colon. Since eosinophils are often increased in the colon of patients with UC the aim of this study was to assess a putative interaction between mast cells, CRF and eosinophils in the mucosal barrier dysfunction of UC.

Material and methods: Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers (51Cr-EDTA, FITC-dextran 4000) were studied in non-inflamed colonic mucosal biopsies from 26 UC patients and 53 controls mounted in Ussing chambers. Permeability studies were complemented by fluorescence microscopy of human tissues and mechanistic studies using human eosinophils (15HL-60), mast cells (HMC-1) and the T84 colonic epithelial cell line.

Results: Permeability to protein antigens was significantly increased in UC (2.3±0.4 vs. 0.99±0.2 pmol/cm2/h; p < 0.01), and was blocked by atropine, α-helicalCRF(9–41) (CRF receptor antagonist), and lodoxamide (mast cell stabilizer). Eosinophils were increased in number in UC and were the dominant mucosal cell type expressing M2 and M3 muscarinic receptors, and displayed immunoreactivity to CRF. Co-culture studies demonstrated that carbachol-activation of 15HL-60 eosinophils resulted in CRF production and mast cell activation, leading to increased T84 epithelial cell permeability to macromolecules.

Conclusion: Our data delineate a novel neuro-immune (cholinergic nerves-eosinophils-mast cells) intercellular circuit, leading to colonic mucosal barrier dysfunction in UC, which may be involved in exacerbation of mucosal inflammation.