Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohn's Ileitis

Joanne C. Masterson, Kelley E. Capocelli, Lindsay Hosford, Kathryn Biette, Eoín N. McNamee, Edwin F. De Zoeten, Rachel Harris, Shahan D. Fernando, Paul Jedlicka, Cheryl Protheroe, James J. Lee, Glenn T. Furuta

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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 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. Antieosinophil therapy was also administered to the Crohn's-like ileitis model (SAMP1/SkuSlc). Results: Our novel eosinophil peroxidase 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 peroxidase secretion and IL-13 production. Exposure to eosinophils in the presence of IL-33, "primed" fibroblasts to increase proinflammatory cytokines (TNF-α, IL-1β, and IL-6), eosinophil-associated chemokines (CCL24 and CCL26), and IL-13Rα2 production. Production of fibrogenic molecules (collagen 1A2, fibronectin, and periostin) increased after 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 that these may contribute to the perpetuation of inflammation and subsequent stricture in pediatric CD.

Original languageEnglish (US)
Pages (from-to)2429-2440
Number of pages12
JournalInflammatory bowel diseases
Volume21
Issue number10
DOIs
StatePublished - Jul 20 2015

Keywords

  • eosinophil
  • fibrosis
  • pediatric Crohn's disease
  • stricture

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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