scholarly journals E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

2020 ◽  
Author(s):  
Yi Rang Na ◽  
Daun Jung ◽  
Michelle Stakenborg ◽  
Gyo Jeong Gu ◽  
Mi Reu Jeong ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Intestinal Inflammation ◽  
Mucosal Healing ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Prostanoid Receptor ◽  
Cell Niche ◽  
Intestinal Macrophage ◽  
Differentiation And Proliferation

AbstractDysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of resolution of inflammation but the mechanisms underlying their mucosal healing capacity remains elusive. Here, we describe a subset of E prostanoid receptor 4 (EP4) expressing intestinal macrophages with mucosal healing properties both in human and mice. Notably, Csf1r-iCre EP4-fl/fl mice showed defective mucosal healing and intestinal epithelial barrier regeneration in a dextran sodium sulfate-induced colitis model. Mechanistically, an increased mucosal level of prostaglandin E2 (PGE2) triggers the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in monocyte-derived EP4+ macrophages via MAPKs. Subsequently, CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during the resolution phase of colitis. Thus, EP4+ intestinal macrophages are essential for the support of the intestinal stem cell niche and for the regeneration of the injured epithelium.One Sentence SummaryProstaglandin E2 licenses E-type prostanoid receptor 4 intestinal macrophage regenerative capacity promoting mucosal healing via the secretion of CXCL1

scholarly journals Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322146
Author(s):  
Yi Rang Na ◽  
Daun Jung ◽  
Michelle Stakenborg ◽  
Hyeri Jang ◽  
Gyo Jeong Gu ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Mucosal Healing ◽  
Epithelial Barrier ◽  
Prostaglandin E ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Regeneration ◽  
Dss Colitis ◽  
Differentiation And Proliferation

ObjectiveDysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive.DesignWe investigated the role of the prostaglandin E2 (PGE2) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. We studied mucosal healing and intestinal epithelial barrier regeneration in Csf1r-iCre Ptger4fl/fl mice during dextran sulfate sodium (DSS)-induced colitis. The effect of PTGER4+ macrophage secreted molecules was investigated on epithelial organoid differentiation.ResultsHere, we describe a subset of PTGER4-expressing intestinal macrophages with mucosal healing properties both in humans and mice. Csf1r-iCre Ptger4fl/fl mice showed defective mucosal healing and epithelial barrier regeneration in a model of DSS colitis. Mechanistically, an increased mucosal level of PGE2 triggers chemokine (C-X-C motif) ligand 1 (CXCL1) secretion in monocyte-derived PTGER4+ macrophages via mitogen-activated protein kinases (MAPKs). CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during colitis. Specific therapeutic targeting of macrophages with liposomes loaded with an MAPK agonist augmented the production of CXCL1 in vivo in conditional macrophage PTGER4-deficient mice, restoring their defective epithelial regeneration and favouring mucosal healing.ConclusionPTGER4+ intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium. Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favour remission in patients with IBD.

scholarly journals Intestinal Mucosal Wound Healing and Barrier Integrity in IBD–Crosstalk and Trafficking of Cellular Players

2021 ◽  
Vol 8 ◽  
Author(s):  
Katrin Sommer ◽  
Maximilian Wiendl ◽  
Tanja M. Müller ◽  
Karin Heidbreder ◽  
Caroline Voskens ◽  
...  
Keyword(s):  
Wound Healing ◽  
Immune Cells ◽  
Wound Repair ◽  
Intestinal Inflammation ◽  
Healing Process ◽  
Epithelial Barrier ◽  
Wound Healing Process ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Mucosal Wound

The intestinal epithelial barrier is carrying out two major functions: restricting the entry of potentially harmful substances while on the other hand allowing the selective passage of nutrients. Thus, an intact epithelial barrier is vital to preserve the integrity of the host and to prevent development of disease. Vice versa, an impaired intestinal epithelial barrier function is a hallmark in the development and perpetuation of inflammatory bowel disease (IBD). Besides a multitude of genetic, molecular and cellular alterations predisposing for or driving barrier dysintegrity in IBD, the appearance of intestinal mucosal wounds is a characteristic event of intestinal inflammation apparently inducing breakdown of the intestinal epithelial barrier. Upon injury, the intestinal mucosa undergoes a wound healing process counteracting this breakdown, which is controlled by complex mechanisms such as epithelial restitution, proliferation and differentiation, but also immune cells like macrophages, granulocytes and lymphocytes. Consequently, the repair of mucosal wounds is dependent on a series of events including coordinated trafficking of immune cells to dedicated sites and complex interactions among the cellular players and other mediators involved. Therefore, a better understanding of the crosstalk between epithelial and immune cells as well as cell trafficking during intestinal wound repair is necessary for the development of improved future therapies. In this review, we summarize current concepts on intestinal mucosal wound healing introducing the main cellular mediators and their interplay as well as their trafficking characteristics, before finally discussing the clinical relevance and translational approaches to therapeutically target this process in a clinical setting.

scholarly journals Baitouweng Decoction Ameliorates Ulcerative Colitis in Mice Partially Attributed to Regulating Th17/Treg Balance and Restoring Intestinal Epithelial Barrier

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiwei Miao ◽  
Liping Chen ◽  
Hui Feng ◽  
Mingjia Gu ◽  
Jing Yan ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Intestinal Inflammation ◽  
Clinical Symptoms ◽  
Activity Index ◽  
Treg Cells ◽  
Raw 264.7 Cells ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Colon Tissue

Ulcerative colitis (UC) is a chronic intestinal disease with unclear pathogenesis. With an increasing global prevalence over the past two decades, UC poses a serious threat to public health. Baitouweng decoction (BTW), a traditional Chinese medicine, has been shown to have good clinical efficacy for treating intestinal inflammation. Yet, the efficacy of BTW in UC and the underlying mechanism remain unclear. The current study aimed to determine whether BTW suppressed intestinal inflammation in mice and the potential mechanism. We used a dextran sulfate sodium (DSS)-induced murine colitis model to test the anti-inflammatory efficacy of BTW. Clinical symptoms were scored by the disease activity index (DAI), and the colon length and pathological changes in colon tissue were also used to further evaluate the efficacy of BTW. Precisely how BTW affected immune function and the intestinal barrier of UC mice was also examined. BTW significantly reduced DAI score and colonic pathological damage. BTW regulated the balance between T helper (Th)17 and regulatory T (Treg) cells, decreased interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, and increased IL-10 levels. BTW reduced intestinal permeability of UC mice, increased expression of tight junction proteins (occludin and zonula occludens-1), and decreased expression of phospho-nuclear factor (p-NF)-κB and phospho-extracellular signal-regulated kinase (p-ERK) in the colon. BTW inhibited the ERK/p-NF-κB signaling pathway and suppressed expression of cyclo-oxygenase-2 and inducible NO synthase in lipopolysaccharide-activated RAW 264.7 cells. BTW significantly promoted the synthesis of short-chain fatty acids in the gut, particularly acetate, propionate, isobutyric acid, and isovalerate. The results suggest that BTW can protect against DSS-induced UC. The mechanism may be partially attributed to regulating the balance of Th17/Treg cells and restoring the intestinal epithelial barrier.

scholarly journals A Novel Pharmacological Approach to Enhance the Integrity and Accelerate Restitution of the Intestinal Epithelial Barrier

2020 ◽  
Vol 26 (9) ◽  
pp. 1340-1352
Author(s):  
Xuelei Cao ◽  
Lei Sun ◽  
Susana Lechuga ◽  
Nayden G Naydenov ◽  
Alex Feygin ◽  
...  
Keyword(s):  
Wound Healing ◽  
Epithelial Cell ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Cell Monolayers ◽  
Barrier Disruption ◽  
Epithelial Cell Monolayers ◽  
Immunofluorescence Labeling ◽  
E Cadherin

Abstract Background Disruption of the gut barrier is an essential mechanism of inflammatory bowel diseases (IBDs) contributing to the development of mucosal inflammation. A hallmark of barrier disruption is the disassembly of epithelial adherens junctions (AJs) driven by decreased expression of a major AJ protein, E-cadherin. A group of isoxazole compounds, such as E-cadherin-upregulator (ECU) and ML327, were previously shown to stimulate E-cadherin expression in poorly differentiated human cancer cells. This study was designed to examine whether these isoxazole compounds can enhance and protect model intestinal epithelial barriers in vitro. Methods The study was conducted using T84, SK-CO15, and HT-29 human colonic epithelial cell monolayers. Disruption of the epithelial barrier was induced by pro-inflammatory cytokines, tumor necrosis factor-α, and interferon-γ. Barrier integrity and epithelial junction assembly was examined using different permeability assays, immunofluorescence labeling, and confocal microscopy. Epithelial restitution was analyzed using a scratch wound healing assay. Results E-cadherin-upregulator and ML327 treatment of intestinal epithelial cell monolayers resulted in several barrier-protective effects, including reduced steady-state epithelial permeability, inhibition of cytokine-induced barrier disruption and junction disassembly, and acceleration of epithelial wound healing. Surprisingly, these effects were not due to upregulation of E-cadherin expression but were mediated by multiple mechanisms including inhibition of junction protein endocytosis, attenuation of cytokine-induced apoptosis, and activation of promigratory Src and AKT signaling. Conclusions Our data highlight ECU and ML327 as promising compounds for developing new therapeutic strategies to protect the integrity and accelerate the restitution of the intestinal epithelial barrier in IBD and other inflammatory disorders.

The enteric nervous system as a regulator of intestinal epithelial barrier function in health and disease

2010 ◽  
Vol 4 (5) ◽  
pp. 637-651 ◽  
Author(s):  
Susanne A Snoek ◽  
Marleen I Verstege ◽  
Guy E Boeckxstaens ◽  
René M van den Wijngaard ◽  
Wouter J de Jonge
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Barrier Function ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Health And Disease
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