scholarly journals Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

2017 ◽  
Vol 214 (6) ◽  
pp. 1737-1752 ◽  
Author(s):  
Viola Neudecker ◽  
Moritz Haneklaus ◽  
Owen Jensen ◽  
Ludmila Khailova ◽  
Joanne C. Masterson ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Nlrp3 Inflammasome ◽  
Untranslated Region ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Innate Immune ◽  
Mouse Line ◽  
Preclinical Models ◽  
Inflammatory Monocytes ◽  
Inflammatory Bowel

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.

scholarly journals Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2645
Author(s):  
Dinh Nam Tran ◽  
Seon Myeong Go ◽  
Seon-Mi Park ◽  
Eui-Man Jung ◽  
Eui-Bae Jeung
Keyword(s):  
Immune Response ◽  
Cellular Proliferation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Innate Immune ◽  
Inflammatory Conditions ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

scholarly journals ErbB-1 experssion in experimental model of inflammatory bowel disease in rats

2004 ◽  
Vol 51 (2) ◽  
pp. 85-89 ◽  
Author(s):  
R. Trzcinski ◽  
M. Bry ◽  
W. Krajewska ◽  
M. Kulig ◽  
A. Dzyiki
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Growth Factor Receptor ◽  
Experimental Colitis ◽  
Altered Level ◽  
Pcr Products ◽  
Epidermal Growth ◽  
Inflammatory Bowel ◽  
Specific Symptoms

Background Ulcerative colitis (UC) and Crohn?s disease (CD) belong to inflammatory bowel disease (IBD). The etiology of IBD is still unknown. Therapy remains empiric or is used for the relief of specific symptoms. The erbB-1 oncogene coding epidermal growth factor receptor (EGFR) is typed as a prognostic marker in several benign and malignant tissues. The aim of our study was to examine the erbB-1 expression in experimental surgically performed model of IBD in rats and to find out if there is any correlation between severity of the intestinal inflammation and altered level of erbB-1 expression. After inducing an experimental colitis samples were taken from different parts of the intestine in all studied groups of rats for histopathology. ErbB-1 mRNA expression was estimated by RT-PCR. PCR products were separated on a 1,5% TBE-agarose gel and visualized with ethidium bromide. The integrated optical density (IOD) of electrophoretically separated amplification products was measured using a video densitometer and Gel-Pro 3.0 software. Nonparametrical statistical test has been used throughout in analyzing the results. Relative erbB-1 expression was determined by comparing to cyclophiline expression. Results Microscopic changes were similar to those observed in IBD. ErbB-1 expression was significantly higher in inflamed tissues of the bowel ( P=0.04 for the transverse colon and P=0.027 for the cecum). Significantly higher erbB-1 expression in inflamed tissues of the bowel suggests that EGFR overexpression may play a role in the pathogenesis of IBD. Overexpression of erbB-1 correlates with the severity of inflammation in bowel tissues.

scholarly journals PPARγin Inflammatory Bowel Disease

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Vito Annese ◽  
Francesca Rogai ◽  
Alessia Settesoldi ◽  
Siro Bagnoli
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Potential Role ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Inflammatory Bowel

Peroxisome proliferator-activated receptor gamma (PPARγ) is member of a family of nuclear receptors that interacts with nuclear proteins acting as coactivators and corepressors. The colon is a major tissue which expresses PPARγin epithelial cells and, to a lesser degree, in macrophages and lymphocytes and plays a role in the regulation of intestinal inflammation. Indeed, both natural and synthetic PPARγligands have beneficial effects in different models of experimental colitis, with possible implication in the therapy of inflammatory bowel disease (IBD). This paper will specifically focus on potential role of PPARγin the predisposition and physiopathology of IBD and will analyze its possible role in medical therapy.

scholarly journals Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

2018 ◽  
Author(s):  
Stefan Grathwohl ◽  
Emmanuel Quansah ◽  
Nazia Maroof ◽  
Jennifer A. Steiner ◽  
Liz Spycher ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Transgenic Mice ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Alpha Synuclein ◽  
Brain Pathology ◽  
Inflammatory Bowel ◽  
Immune Pathways ◽  
The Brain

AbstractIntraneuronal accumulation of α-synuclein (αSyn) is key in the pathogenesis of Parkinson’s disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of αSyn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit αSyn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger αSyn accumulation in the ENS of wildtype and αSyn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of αSyn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old αSyn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

scholarly journals Microbial Sensing by the Intestinal Epithelium in the Pathogenesis of Inflammatory Bowel Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Michael Scharl ◽  
Gerhard Rogler
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune System ◽  
Intestinal Microbiota ◽  
Bowel Disease ◽  
Innate Immune System ◽  
Pathogenic Bacteria ◽  
Intestinal Inflammation ◽  
Innate Immune ◽  
Model Systems ◽  
Inflammatory Bowel

Recent years have raised evidence that the intestinal microbiota plays a crucial role in the pathogenesis of chronic inflammatory bowels diseases. This evidence comes from several observations. First, animals raised under germ-free conditions do not develop intestinal inflammation in several different model systems. Second, antibiotics are able to modulate the course of experimental colitis. Third, genetic polymorphisms in a variety of genes of the innate immune system have been associated with chronic intestinal inflammatory diseases. Dysfunction of these molecules results in an inappropriate response to bacterial and antigenic stimulation of the innate immune system in the gastrointestinal tract. Variants of pattern recognition receptors such as NOD2 or TLRs by which commensal and pathogenic bacteria can be detected have been shown to be involved in the pathogenesis of IBD. But not only pathways of microbial detection but also intracellular ways of bacterial processing such as autophagosome function are associated with the risk to develop Crohn's disease. Thus, the “environment concept” and the “genetic concept” of inflammatory bowel disease pathophysiology are converging via the intestinal microbiota and the recognition mechanisms for an invasion of members of the microbiota into the mucosa.

scholarly journals The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease

2012 ◽  
Vol 302 (5) ◽  
pp. G484-G492 ◽  
Author(s):  
Sarah A. Ingersoll ◽  
Saravanan Ayyadurai ◽  
Moiz A. Charania ◽  
Hamed Laroui ◽  
Yutao Yan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Innate Immune ◽  
Peptide Transport ◽  
Innate Immune Responses ◽  
Colon Cells ◽  
Proinflammatory Responses ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Intestinal inflammation is characterized by epithelial disruption, leading to loss of barrier function and the recruitment of immune cells, including neutrophils. Although the mechanisms are not yet completely understood, interactions between environmental and immunological factors are thought to be critical in the initiation and progression of intestinal inflammation. In recent years, it has become apparent that the di/tripeptide transporter PepT1 may play an important role in the pathogenesis of such inflammation. In healthy individuals, PepT1 is primarily expressed in the small intestine and transports di/tripeptides for metabolic purposes. However, during chronic inflammation such as that associated with inflammatory bowel disease, PepT1 expression is upregulated in the colon, wherein the protein is normally expressed either minimally or not at all. Several recent studies have shown that PepT1 binds to and transports various bacterial di/tripeptides into colon cells, leading to activation of downstream proinflammatory responses via peptide interactions with innate immune receptors. In the present review, we examine the relationship between colonic PepT1-mediated peptide transport in the colon and activation of innate immune responses during disease. It is important to understand the mechanisms of PepT1 action during chronic intestinal inflammation to develop future therapies addressing inappropriate immune activation in the colon.

scholarly journals Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis

2020 ◽  
Vol 21 (21) ◽  
pp. 8145
Author(s):  
Kohei Wagatsuma ◽  
Hiroshi Nakase
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Nlrp3 Inflammasome ◽  
Experimental Colitis ◽  
Regulatory Mechanisms ◽  
Pyrin Domain ◽  
Complex Interactions ◽  
Inflammatory Bowel ◽  
Receptor Family

The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.

scholarly journals CCR8 Signaling via CCL1 Regulates Responses of Intestinal IFN-γ Producing Innate Lymphoid CelIs and Protects From Experimental Colitis

2021 ◽  
Vol 11 ◽  
Author(s):  
Le Kang ◽  
Angelika Schmalzl ◽  
Tamara Leupold ◽  
Miguel Gonzalez-Acera ◽  
Raja Atreya ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Lymphoid Cells ◽  
Protective Function ◽  
Inflammatory Bowel ◽  
Ifn Γ

A diverse spectrum of immune cells populates the intestinal mucosa reflecting the continuous stimulation by luminal antigens. In lesions of patients with inflammatory bowel disease, an aberrant inflammatory process is characterized by a very prominent infiltrate of activated immune cells producing cytokines and chemokines. These mediators perpetuate intestinal inflammation or may contribute to mucosal protection depending on the cellular context. In order to further characterize this complex immune cell network in intestinal inflammation, we investigated the contribution of the chemokine receptor CCR8 to development of colitis using a mouse model of experimental inflammation. We found that CCR8−/− mice compared to wildtype controls developed strong weight loss accompanied by increased histological and endoscopic signs of mucosal damage. Further experiments revealed that this gut protective function of CCR8 seems to be selectively mediated by the chemotactic ligand CCL1, which was particularly produced by intestinal macrophages during colitis. Moreover, we newly identified CCR8 expression on a subgroup of intestinal innate lymphoid cells producing IFN-γ and linked a functional CCL1/CCR8 axis with their abundance in the gut. Our data therefore suggest that this pathway supports tissue-specific ILC functions important for intestinal homeostasis. Modulation of this regulatory circuit may represent a new strategy to treat inflammatory bowel disease in humans.

scholarly journals Elevated Expression of AXL May Contribute to the Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Éva Boros ◽  
Zoltán Kellermayer ◽  
Péter Balogh ◽  
Gerda Strifler ◽  
Andrea Vörös ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Mesenchymal Transition ◽  
Inflammatory Bowel ◽  
Chronic Intestinal Inflammation

Understanding the molecular mechanisms inducing and regulating epithelial-to-mesenchymal transition (EMT) upon chronic intestinal inflammation is critical for understanding the exact pathomechanism of inflammatory bowel disease (IBD). The aim of this study was to determine the expression profile of TAM family receptors in an inflamed colon. For this, we used a rat model of experimental colitis and also collected samples from colons of IBD patients. Samples were taken from both inflamed and uninflamed regions of the same colon; the total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that AXL is highly induced in active-inflamed colon, which is accompanied with reduced expression of AXL-regulating microRNAs. In addition, the expression of genes responsible for inducing or maintaining mesenchymal phenotype, such as SNAI1, ZEB2, VIM, MMP9, and HIF1α, were all significantly induced in the active-inflamed colon of IBD patients while the epithelial marker E-cadherin (CDH1) was downregulated. We also show that, in vitro, monocytic and colonic epithelial cells increase the expression of AXL in response to LPS or TNFα stimuli, respectively. In summary, we identified several interacting genes and microRNAs with mutually exclusive expression pattern in active-inflamed colon of IBD patients. Our results shed light onto a possible AXL- and microRNA-mediated regulation influencing epithelial-to-mesenchymal transition in IBD.

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