Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease

Wehkamp, Jan; Koslowski, Maureen J.; Wang, G; Stange, Eduard F.

doi:10.1038/mi.2008.48

Cited by 118 publications

(110 citation statements)

References 57 publications

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“…Secretion of antimicrobial peptides by Paneth cells is an important protective mechanism by which intestinal immune homeostasis is established 28,29 , and defects in Paneth cell function have been described in IBD patients 30,31 35 . In addition, mice defective in ER stress signalling or autophagy, such as XBP1 IEC-KO mice 36 and hypomorphic ATG16L1 mice 37 , respectively, display Paneth cell abnormalities.…”

Section: Discussionmentioning

confidence: 99%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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The transcription factor NF-kB is indispensable for intestinal immune homeostasis, but contributes to chronic inflammation and inflammatory bowel disease (IBD). A20, an inhibitor of both NF-kB and apoptotic signalling, was identified as a susceptibility gene for multiple inflammatory diseases, including IBD. Despite absence of spontaneous intestinal inflammation in intestinal epithelial cell (IEC) specific A20 knockout mice, we found additional myeloid-specific A20 deletion to synergistically drive intestinal pathology through cell-specific mechanisms. A20 ensures intestinal barrier stability by preventing cytokine-induced IEC apoptosis, while A20 prevents excessive cytokine production in myeloid cells. Combining IEC and myeloid A20 deletion induces ileitis and severe colitis, characterized by IEC apoptosis, Paneth and goblet cell loss, epithelial hyperproliferation and intestinal microbiota dysbiosis. Continuous epithelial cell death and regeneration in an inflammatory environment sensitizes cells for neoplastic transformation and the development of colorectal tumours in aged mice.

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Section: Discussionmentioning

confidence: 99%

A20 controls intestinal homeostasis through cell-specific activities

et al. 2014

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“…IEC have the ability to recognize pathogens through innate immune receptors, re- spond by releasing antimicrobial peptides (26), and modulate initial events of the immune response by, for example, secretion of pro/anti-inflammatory mediators and cytokines (27). The IECspecific increase of IL-33 in inflamed UC colons and SAMP ilea, particularly the 30-kDa form with increased proinflammatory activity (11), may be a consequence of interactions with commensal and/or luminal pathogens, thereby triggering inflammatory responses and perpetuating a chronic, Th2-mediated colitis.…”

Section: Discussionmentioning

confidence: 99%

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

Pastorelli

Garg

Hoang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

366

395

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IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.inflammatory bowel disease | anti-TNF therapy | SAMP1/YitFc mouse model

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“…TNF-␣ and Sdc1 acted synergistically in this process. Since the epithelial barrier function is essential for the pathogenesis of IBD, 42 and given these data, it can be speculated that challenging the animals with DSS, triggering TNF-␣ production (especially in a system already lacking the protective factor of Sdc1 for the gut) promoted lethality in our model.…”

Section: Sdc1 and Intestinal Inflammationmentioning

confidence: 99%

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Floer

Götte

Wild

et al. 2010

The American Journal of Pathology

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Syndecan-1 (Sdc1) plays a major role in wound healing and modulates inflammatory responses. Sdc1 expression is reduced in lesions of patients with ulcerative colitis. The aim of this study was to investigate the role of Sdc1 in murine dextran sodium sulfate (DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient (knockout (KO)) and wild-type mice by oral administration of 3% DSS. KO mice exhibited a significantly increased lethality as compared with wild-type controls (61 versus 5% , P < 0.05). Impaired mucosal healing and prolonged recruitment of inflammatory cells in KO mice were accompanied by significant up-regulation of tumor necrosis factor-␣, CC chemokine ligand 3/macrophage inflammatory protein-1␣, and vascular cell adhesion molecule-1 , as determined by histological correlation between 0 and 15 days after colitis induction , TaqMan low-density array analysis , and quantitative real-time PCR. Treatment from days 7 through 14 with enoxaparin , a functional analogue of the Sdc1 heparan sulfate chains , significantly reduced lethality of KO mice due to DSS-induced colitis , which was correlated with improved mucosal healing. In vitro, Sdc1-deficient polymorphonuclear cells displayed increased adhesion to endothelial cells and intercellular adhesion molecule-1, and enoxaparin reverted adhesion to wild-type levels. Small interfering RNA-mediated knockdown of Sdc1 expression resulted in reduced basic fibroblast growth factor-mediated mitogen-activated protein kinase signaling and reduced Caco-2 cell proliferation. We conclude that Sdc1 has a protective effect during experimental colitis. The modification of missing Sdc1 function by heparin analogues may emerge as a promising anti-inflammatory approach. (Am J Pathol

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Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease

Cited by 118 publications

References 57 publications

A20 controls intestinal homeostasis through cell-specific activities

A20 controls intestinal homeostasis through cell-specific activities

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

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