IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo

Scheibe, Kristina; Backert, Ingo; Wirtz, Stefan; Hueber, Axel J.; Schett, Georg; Vieth, Michael; Probst, Hans Christian; Bopp, Tobias; Neurath, Markus F.; Neufert, Clemens

doi:10.1136/gutjnl-2015-310374

Cited by 154 publications

(206 citation statements)

References 46 publications

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“…DSS-induced colitis model was established using a method described previously 24 25. Briefly, WT and CD177 −/− mice (n=12 per group) were given 2.0% DSS (molecular mass, 36 000–50 000, MP Biomedicals, Solon, Ohio, USA) in the drinking water for continuous 7 days, then followed with regular water for another 3 days.…”

Section: Methodsmentioning

confidence: 99%

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

Zhou

Lin

Fang

et al. 2017

Gut

181

149

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Section: Methodsmentioning

confidence: 99%

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

Zhou

Lin

Fang

et al. 2017

Gut

181

149

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“…184,185 The protective effects of IL36 ligands in the epithelium might depend, in part, on IL22-mediated induction of the antimicrobial peptides S100A8/9 and regenerating islet-derived 3 gamma (REG3G). IL10 is also involved in the epithelial restitution induced during intestinal inflammation.…”

Section: Inflammation and Restoration Of Mucosal Barrier Functionmentioning

confidence: 99%

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

2016

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The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte–epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation.

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“…IL‐36 family cytokines (IL‐36α, IL‐36β and IL‐36γ), which belong to the IL‐1 super‐family, have recently emerged as key regulators of immune responses at mucosal sites . They are expressed by a range of cell types, including mucosal epithelial cells, macrophages and dendritic cells, and induced in response to TLR signaling .…”

Section: Introductionmentioning

confidence: 99%

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

et al. 2018

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Interleukin (IL)-36 cytokines are important regulators of mucosal homeostasis and inflammation. We previously established that oral epithelial cells strongly upregulate IL-36γ expression in response to the bacterial pathogen Porphyromonas gingivalis. Here, we have established that IL-36γ stimulates the expression of the IL-12 cytokine family members, IL-23p19 and Epstein-Barr Virus-Induced Gene 3 (EBI3), by oral epithelial cells; their expression was also selectively stimulated by IL-36α. Notably, IL-23p19 and EBI3 expression was not stimulated by P. gingivalis, thus suggesting that their expression by the oral epithelium in response to P. gingivalis is likely to be mediated in an autocrine manner by IL-36γ. The IL-36γ-inducible expression of IL-23p19 and EBI3 was found to be diametrically regulated by the mitogen-activated protein kinase/extracellular signal regulated kinase (MEK)-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereby the activation of MEK-ERK signaling likely functions as a negative feedback mechanism to limit EBI3 expression. Furthermore, epidermal growth factor receptor (EGFR) signaling, which is important for mucosal homeostasis, was demonstrated to modulate, in a MEK-ERK-dependent manner, the stimulation of IL-23p19 and EBI3 expression by IL-36γ. IL-23p19 and EBI3 have recently been shown to heterodimerize to form the novel cytokine IL-39 and promote neutrophil expansion. EBI3 has been shown to also have IL-12 cytokine family independent functions (e.g. mediating IL-6 trans-signaling). Thus, this study not only advances our understanding of how IL-36 cytokines may control mucosal inflammation, but also establishes EGFR signaling as a potentially important modulator of IL-36 cytokine function.

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IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo

Abstract: IL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.

Cited by 154 publications

References 46 publications

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

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IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo

Abstract: IL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.

Cited by 154 publications

References 46 publications

CD177+neutrophils as functionally activated neutrophils negatively regulate IBD

CD177+neutrophils as functionally activated neutrophils negatively regulate IBD

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

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Resources

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CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD

CD177⁺neutrophils as functionally activated neutrophils negatively regulate IBD