scholarly journals Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation

2021 ◽  
Author(s):  
Christa Kietz ◽  
Aravind K. Mohan ◽  
Vilma Pollari ◽  
Ida-Emma Tuominen ◽  
Paulo S. Ribeiro ◽  
...  
Keyword(s):  
Immune Responses ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Fat Body ◽  
Stable Complex ◽  
Transgenic Expression ◽  
Effector Caspase ◽  
Axenic Conditions ◽  
Inflammatory Signalling ◽  
Chronic Intestinal Inflammation

AbstractThe Drosophila IAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophila midgut, but not in the fat body. Drice is a Drosophila effector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine.

scholarly journals drICE restrains DIAP2-mediated inflammatory signalling and intestinal inflammation

2020 ◽  
Author(s):  
Christa Kietz ◽  
Vilma Pollari ◽  
Ida-Emma Tuominen ◽  
Paulo S Ribeiro ◽  
Pascal Meier ◽  
...  
Keyword(s):  
Immune Responses ◽  
Target Gene ◽  
Intestinal Inflammation ◽  
Fat Body ◽  
Gene Activation ◽  
Induced Responses ◽  
Regulatory Effect ◽  
Transgenic Expression ◽  
Intestinal Epithelia ◽  
Inflammatory Signalling

AbstractThe Drosophila IAP protein, DIAP2, is a key mediator of NF-κB signalling and is required for immune activation, both locally in the intestinal epithelia and during systemic, fat body-induced responses. We have found that transgenic expression of DIAP2 induces inflammation in the intestine, but not in the fat body, indicating a need for regulating DIAP2 in microbiotic environments. We describe the Drosophila caspase drICE, a known interaction partner of DIAP2, as a regulator of DIAP2 and NF-κB signalling in the intestinal epithelium. drICE acts by cleaving, and interfering with DIAP2’s ability to ubiquitinate and, thereby, activate mediators of the NF-κB pathway. The drICE-cleaved form of DIAP2 is, moreover, unable to induce inflammation during basal conditions in the intestine. Interestingly, cleavage of DIAP2 does not interfere with pathogen-induced signalling, suggesting that drICE protects from immune responses induced by resident microbes. Accordingly, the negative regulatory effect of drICE is lost when rearing flies axenic. Hence, we show that drICE halts unwanted inflammatory signalling in the intestine by forming an inhibitory complex with DIAP2, interfering with the ability of DIAP2 to induce downstream signalling and NF-κB target gene activation.

scholarly journals Inflammation-Induced Acid Tolerance GenesgadABin Luminal Commensal Escherichia coli Attenuate Experimental Colitis

2013 ◽  
Vol 81 (10) ◽  
pp. 3662-3671 ◽  
Author(s):  
Sandrine Tchaptchet ◽  
Ting-Jia Fan ◽  
Laura Goeser ◽  
Alexi Schoenborn ◽  
Ajay S. Gulati ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Acid Tolerance ◽  
Experimental Colitis ◽  
Intestinal Epithelial ◽  
Content Type ◽  
E Coli ◽  
Chronic Intestinal Inflammation

ABSTRACTDysregulated immune responses to commensal intestinal bacteria, includingEscherichia coli, contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally,E. coliresponds to chronic intestinal inflammation by upregulating expression of stress response genes, includinggadAandgadB. GadAB encode glutamate decarboxylase and protectE. colifrom the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with active IBDs. We hypothesized thatE. coliupregulatesgadABduring inflammation to enhance its survival and virulence. Using real-time PCR, we determinedgadABexpression in luminalE. colifrom ex-germfree wild-type (WT) and interleukin-10 (IL-10) knockout (KO) (IL-10−/−) mice selectively colonized with a commensalE. coliisolate (NC101) that causes colitis in KO mice in isolation or in combination with 7 other commensal intestinal bacterial strains.E. colisurvival and host inflammatory responses were measured in WT and KO mice colonized with NC101 or a mutant lacking thegadABgenes (NC101ΔgadAB). The susceptibility of NC101 and NC101ΔgadABto killing by host antimicrobial peptides and their translocation across intestinal epithelial cells were evaluated using bacterial killing assays and transwell experiments, respectively. We show that expression ofgadABin luminalE. coliincreases proportionately with intestinal inflammation in KO mice and enhances the susceptibility of NC101 to killing by the host antimicrobial peptide cryptdin-4 but decreases bacterial transmigration across intestinal epithelial cells, colonic inflammation, and mucosal immune responses. Chronic intestinal inflammation upregulates acid tolerance pathways in commensalE. coliisolates, which, contrary to our original hypothesis, limits their survival and colitogenic potential. Further investigation of microbial adaptation to immune-mediated inflammation may provide novel insights into the pathogenesis and treatment of IBDs.

scholarly journals Regulation of Mucosal Immune Responses – The Missing Link in IBD?

1996 ◽  
Vol 10 (2) ◽  
pp. 105-109
Author(s):  
Charles O Elson ◽  
Robert P Mccabe ◽  
Kenneth W Beagley ◽  
Almaz Sharmanov ◽  
Steven L Brandwein ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Intestinal Inflammation ◽  
Bacterial Flora ◽  
Cell Subset ◽  
Experimental Models ◽  
Bacterial Antigens ◽  
Mucosal Immune Responses ◽  
Chronic Intestinal Inflammation

Although the etiology of inflammatory bowel disease (IBD) remains unknown, a major working hypothesis is that it represents a dysregulated immune response to common enteric bacterial antigens. Until recently there has been a relative dearth of experimental models to study this hypothesis. However, exciting developments in experimental models of colitis, including spontaneous, transgenic and knockout mice, now allow this and other hypotheses to be tested. The regulation of mucosal immune responses is not well understood in the normal animal, much less in those with chronic intestinal inflammation. Clearly the CD4 Th1 and Th2 pathways are important in the host response to microbial pathogens, and recent data indicate that the intestinal mucosa seems to be a site of preferential Th2 responses toward exogenous antigens. Deletion of certain cytokine genes involved in maintaining this Th1/Th2 balance (interleukin [IL]-2, IL-10) resulted in colitis, although deletion of others (IL-4, interferon-gamma) that are also involved did not. Whether these cytokine gene deletions cause a dysregulation of the mucosal immune response has yet to be shown. However, the importance of regulation can be demonstrated in a model in which a normal CD4+T cell subset (CD45Rbhigh) is transferred into syngeneic severe combined immunodeficiency syndrome recipients. This results in a striking colitis over the ensuing weeks with chronic diarrhea and wasting of the animals. If the reciprocal CD4+subset (CD45Rblow) is co-transferred or if whole CD4+T cells are transferred no colitis ensues. Therefore, T cells capable of causing colitis are present in normal animals but are prevented from doing so by immunoregulatory mechanisms. The antigens that drive the colitis in several of these models (IL-2 knockout mouse, human leukocyte antigen B27/β2M transgenic rat) appear to be those of the normal enteric bacterial flora because germ-free animals do not get the disease. Spontaneously colitic C3H/HeJBir mice also show prominent reactivity to enteric bacterial antigens. There are major differences among inbred mouse strains in susceptibility to colitis. The genes involved are not yet identified, but newly available technologies should allow that. In summary, these new models provide an experimental foundation to one of the major hypotheses on the cause of IBD, and will allow dissection of the genetic, environmental and immune components contributing to chronic colitis.

scholarly journals High-Fat Diet Promotes DSS-Induced Ulcerative Colitis by Downregulated FXR Expression through the TGFB Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Di Zhao ◽  
Chenwen Cai ◽  
Qiyi Chen ◽  
Shuang Jin ◽  
Bo Yang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
High Fat Diet ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Farnesoid X Receptor ◽  
Mucosal Barrier ◽  
High Fat ◽  
Colon Rectal Cancer ◽  
Chronic Intestinal Inflammation

Ulcerative colitis is one of the IBD which cause a chronic intestinal inflammation and dysfunctional of the mucosal barrier. For now, the incident of UC was steadily increased all over the world. It has become a novel independent risk factor of several severe diseases especially colon-rectal cancer. However, the etiology of UC was still obscure. Previous studies show that high-fat diet contributed to the pathogenesis of immune system dysregulation, and farnesoid X receptor (FXR) was also implicated in the pathogenesis of various inflammatory symptoms. Yet, their inner roles in the pathogenesis of UC have not been mentioned. In this study, we aim to investigate the role of FXR in UC. High-fat diet (HFD) promotes the progression of DSS-induced UC, shows an increasing secretion of bile acid in serum, and leads to a downregulation of FXR target genes (FXRα, Shp, and lbabp). Adding FXR agonist FexD rescues the phenotype induced by high-fat diet, whereas TGFBRI inhibitor SB431542 abrogates the restoration by FexD in DSS-induced UC mice. To further verify the relationship between the FXR and TGFB signaling pathway, we made a UC-HFD model in the Caco2 cell line. Results shows the same conclusion that FXR mitigate UC inflammation through a TGFB-dependent pathway. These results expand the role of FXR in ulcerative colitis and suggest that FXR activation may be considered a therapeutic strategy for UC.

scholarly journals SMAD4 governs a feedforward regulation of the TGF-β-effects in CD8 T cells that contributes to preventing chronic intestinal inflammation

2021 ◽  
Author(s):  
Ramdane Igalouzene ◽  
Hector Hernandez-Vargas ◽  
Nicolas Benech ◽  
David Bauché ◽  
Célia Barrachina ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Intestinal Inflammation ◽  
Cd8 T Cell ◽  
Wide Range ◽  
Chronic Intestinal Inflammation

AbstractSMAD4, a key mediator of TGF-β signaling, plays a crucial role in T cells to prevent chronic gut inflammation. However, the molecular mechanisms underlying this control remain elusive. Using different genetic and epigenetic approaches, we unexpectedly reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation by a feedforward mechanism that is TGF-β-independent. Prior to any TGF-β-receptor engagement, SMAD4 acts as an active and basal repressor of epigenetic, transcriptional and functional TGF-β imprinting in CD8 T cells. Thus, in sharp opposition to total TGF-β signaling deletion, SMAD4 deletion impairs naïve CD8 T cell effector predisposition but promotes CD8 T cell accumulation and epithelial retention by promoting their response to IL-7 and their expression of integrins such as Itgae. Besides, SMAD4 deletion unleashes the induction of a wide range of TGF-β-signaling-repressors such as Smad7, Ski, Skil, and Smurf2 and hampers TGF-β-mediated CD8 T cell immunosuppression. Mechanistically, prior to any TGF-β signal, SMAD4 binds to the loci of several TGF-β-target genes, and by regulating histone acetylation, represses their expression. The massive gut epithelial colonization, associated with their escape from the immunoregulatory TGF-β effects overtakes their poor effector preconditioning and elicits microbiota-driven chronic epithelial CD8 T cell activation. Hence, in an anticipatory manner, independently of TGF-β, SMAD4 governs a feedforward regulation of TGF-β effects in CD8 T cells, preventing chronic intestinal inflammation.

Role of CD5 expression on TCRγδ T cell-differentiation and development of chronic intestinal inflammation

2001 ◽  
Vol 120 (5) ◽  
pp. A517-A517
Author(s):  
A MIZOGUCHI ◽  
E MIZOGUCHI ◽  
Y DEJONG ◽  
H TAKEDATSU ◽  
F PREFFER ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Intestinal Inflammation ◽  
T Cell Differentiation ◽  
Chronic Intestinal Inflammation

scholarly journals Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

2021 ◽  
Vol 22 (5) ◽  
pp. 2602
Author(s):  
Emilie Viennois ◽  
Benoit Chassaing
Keyword(s):  
Intestinal Inflammation ◽  
Tumor Development ◽  
Low Grade ◽  
Gastrointestinal Cancers ◽  
Cancer Initiation ◽  
And Function ◽  
The Impact ◽  
Chronic Intestinal Inflammation ◽  
Low Grade Inflammation ◽  
Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

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