title: Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohn's Ileitis.
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.
authors.affiliation: *Section of Pediatric Gastroenterology, Hepatology and Nutrition, Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics and Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado; †Department of Medicine, Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado; ‡University of Colorado School of Medicine, Aurora, Colorado; §Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; ‖Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado; and ¶Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Azusa, California.
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Masterson
authors.forename: Kelley E
authors.initials: KE
authors.lastname: Capocelli
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hosford
authors.forename: Kathryn
authors.initials: K
authors.lastname: Biette
authors.forename: Eóin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Edwin F
authors.initials: EF
authors.lastname: de Zoeten
authors.forename: Rachel
authors.initials: R
authors.lastname: Harris
authors.forename: Shahan D
authors.initials: SD
authors.lastname: Fernando
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Cheryl
authors.initials: C
authors.lastname: Protheroe
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
mesh_terms: D000293:Adolescent; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D003251:Constriction, Pathologic / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004802:Eosinophilia / Q000150:complications* / Q000175:diagnosis; D004804:Eosinophils / Q000502:physiology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007082:Ileum / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D005353:Fibronectins; C506536:IL33 protein, human; D018836:Inflammation Mediators; D018793:Interleukin-13; D000067596:Interleukin-33; C512835:POSTN protein, human; D003094:Collagen; D009195:Peroxidase