Dataset Information

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

ABSTRACT: 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.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).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-?, IL-1?, and IL-6), eosinophil-associated chemokines (CCL24 and CCL26), and IL-13R?2 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.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.

SUBMITTER: Masterson JC

PROVIDER: S-EPMC4567482 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Masterson Joanne C JC Capocelli Kelley E KE Hosford Lindsay L Biette Kathryn K McNamee Eóin N EN de Zoeten Edwin F EF Harris Rachel R Fernando Shahan D SD Jedlicka Paul P Protheroe Cheryl C Lee James J JJ Furuta Glenn T GT

Inflammatory bowel diseases 20151001 10

<h4>Background</h4>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.<h4>Methods</h4>We performed a retrospective study of 74 children with inflammatory and stricturing ileal CD comparing clinicopathological features to immunohistochemical measures of eosinoph ...[more]

PMID: 26218140

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Project description:Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

Dataset Information

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

Publications

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

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