scholarly journals Intestinal-epithelial LSD1 controls goblet cell maturation and effector responses required for gut immunity to bacterial and helminth infection

2021 ◽  
Vol 17 (3) ◽  
pp. e1009476
Author(s):  
Naveen Parmar ◽  
Kyle Burrows ◽  
Pia M. Vornewald ◽  
Håvard T. Lindholm ◽  
Rosalie T. Zwiggelaar ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Cell Biology ◽  
Helminth Infection ◽  
Inflammatory Diseases ◽  
Cell Maturation ◽  
Infection Model ◽  
Critical Element ◽  
Intestinal Epithelial ◽  
Regulatory Enzymes ◽  
Gut Immunity

Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity and can be therapeutically targeted. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with bacteria-induced colitis or a helminth infection model both resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 is important for goblet cell maturation and goblet-cell effector molecules such as RELMß. We propose that this may be in part mediated by directly controlling genes that facilitate cytoskeletal organization, which is important in goblet cell biology. This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from infection.

scholarly journals Intestinal-epithelial LSD1 controls cytoskeletal-mediated cell identity including goblet cell effector responses required for gut inflammatory and infectious diseases

2020 ◽  
Author(s):  
Naveen Parmar ◽  
Kyle Burrows ◽  
Håvard T. Lindholm ◽  
Rosalie T. Zwiggelaar ◽  
Mara Martín-Alonso ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Inflammatory Diseases ◽  
Infection Model ◽  
Critical Element ◽  
Intestinal Epithelial ◽  
Host Protection ◽  
Regulatory Enzymes ◽  
Specific Effector ◽  
Cell Effector

ABSTRACTInfectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with chemical-induced colitis, bacteria-induced colitis, and a helminth infection model all resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 directly controls genes that facilitate cytoskeletal organization, and that this is relevant for epithelial attachment as well as for goblet-cell specific effector responses.This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from inflammation and infection.

scholarly journals PGD2 and CRTH2 counteract Type 2 cytokine–elicited intestinal epithelial responses during helminth infection

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Oyebola O. Oyesola ◽  
Michael T. Shanahan ◽  
Matt Kanke ◽  
Bridget M. Mooney ◽  
Lauren M. Webb ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Goblet Cell ◽  
Helminth Infection ◽  
Intestinal Helminth ◽  
Prostaglandin D2 ◽  
Intestinal Epithelial ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Small Intestinal

Type 2 inflammation is associated with epithelial cell responses, including goblet cell hyperplasia, that promote worm expulsion during intestinal helminth infection. How these epithelial responses are regulated remains incompletely understood. Here, we show that mice deficient in the prostaglandin D2 (PGD2) receptor CRTH2 and mice with CRTH2 deficiency only in nonhematopoietic cells exhibited enhanced worm clearance and intestinal goblet cell hyperplasia following infection with the helminth Nippostrongylus brasiliensis. Small intestinal stem, goblet, and tuft cells expressed CRTH2. CRTH2-deficient small intestinal organoids showed enhanced budding and terminal differentiation to the goblet cell lineage. During helminth infection or in organoids, PGD2 and CRTH2 down-regulated intestinal epithelial Il13ra1 expression and reversed Type 2 cytokine–mediated suppression of epithelial cell proliferation and promotion of goblet cell accumulation. These data show that the PGD2–CRTH2 pathway negatively regulates the Type 2 cytokine–driven epithelial program, revealing a mechanism that can temper the highly inflammatory effects of the anti-helminth response.

scholarly journals Arctigenin fromFructus Arctii(Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Hee Soon Shin ◽  
Sun Young Jung ◽  
Su Yeon Back ◽  
Jeong-Ryong Do ◽  
Dong-Hwa Shon
Keyword(s):  
Barrier Function ◽  
Active Component ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Transepithelial Electrical Resistance ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Traditional Herbal Medicine ◽  
Cell Monolayers ◽  
Basolateral Side

Fructus Arctiiis used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect ofF. Arctiiextract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component ofF. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment ofF. Arctiiincreased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component ofF. Arctiiincreased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed thatF. Arctiicould enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin fromF. Arctiicould contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function.

A further note on the measurement of the affinity of a dye (Azure A) for histological substrates

1965 ◽  
Vol s3-106 (76) ◽  
pp. 299-306
Author(s):  
D. J. GOLDSTEIN
Keyword(s):  
Adsorption Isotherm ◽  
Goblet Cell ◽  
Binding Sites ◽  
Langmuir Isotherm ◽  
Langmuir Adsorption Isotherm ◽  
Intestinal Epithelial ◽  
Langmuir Adsorption ◽  
Azure A ◽  
First Approximation ◽  
The Ideal

If two histological sections, of thickness nµ and 2nµ, and having the same apparent intensity of staining, are at equilibrium with dyebaths of concentration B1 and B2 respectively, the affinity of the histological substrate for the dye is, under denned conditions, given by the expression ΔF° = - RT In I/B, where B is either (i) B2 if the thinner section is stained to saturation, or (ii) B1 if B1 = 3B2. The affinity tends to be greater when measured in a weaker dyebath, as implied in method (ii). Evidence is presented suggesting that the uptake of the basic dye Azure A by pancreatic basal chromidial substance, goblet cell mucin and intestinal epithelial cytoplasm follows a Langmuir adsorption isotherm to a first approximation, in that, at low dyebath concentrations, the uptake of dye is proportional to the concentration of dyebath with which the substrate is in equilibrium, while in strong dyebaths the uptake approaches a plateau. A deviation from the ideal Langmuir isotherm in dyebaths of moderate concentration, observed in epithelial cytoplasm and to a lesser extent in pancreatic basal chromidial substance, may have been due to interaction between neighbouring dye-binding sites, or to the presence in a single area of sites with different affinities for the dye.

scholarly journals Intestinal Epithelial Cell-Intrinsic Deletion of Setd7 Identifies Role for Developmental Pathways in Immunity to Helminth Infection

2016 ◽  
Vol 12 (9) ◽  
pp. e1005876 ◽  
Author(s):  
Menno J. Oudhoff ◽  
Frann Antignano ◽  
Alistair L. Chenery ◽  
Kyle Burrows ◽  
Stephen A. Redpath ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Helminth Infection ◽  
Developmental Pathways ◽  
Intestinal Epithelial

scholarly journals T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Kiekens ◽  
Wouter Van Loocke ◽  
Sylvie Taveirne ◽  
Sigrid Wahlen ◽  
Eva Persyn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Current Knowledge ◽  
Functional Differentiation ◽  
Cell Maturation ◽  
Hematopoietic Stem ◽  
And Function

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.

Stabilization but no functional influence of HIF-1α expression in the intestinal epithelium during Salmonella Typhimurium infection

2022 ◽  
Author(s):  
Laura Robrahn ◽  
Aline Dupont ◽  
Sandra Jumpertz ◽  
Kaiyi Zhang ◽  
Christian H. Holland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intestinal Epithelium ◽  
Bacterial Infections ◽  
Inflammatory Diseases ◽  
Protein Stabilization ◽  
Inflammatory Factors ◽  
Intestinal Epithelial ◽  
Data Set ◽  
The Impact

The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to enhance microbial killing and to ameliorate the course of bacterial infections. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the gastrointestinal tract remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of HIF-1 after oral infection of mice with Salmonella Typhimurium. Immunohistochemistry and western blot analysis confirmed marked HIF-1α protein stabilization, especially in the intestinal epithelium. This prompted us to analyze conditional Hif1a -deficient mice to examine cell type-specific functions of HIF-1 in this model. Our results demonstrate enhanced non-canonical induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells did not impact on inflammatory gene expression, bacterial spread or disease outcome. In contrast, Hif1a deletion in myeloid cells enhanced intestinal Cxcl2 expression and reduced the cecal Salmonella load. In vitro , HIF-1α-deficient macrophages showed an overall impaired transcription of mRNA encoding pro-inflammatory factors, however, intracellular survival of Salmonella was not impacted by HIF-1α deficiency.

scholarly journals Identification of transmembrane protein 237 as a novel interactor with the intestinal riboflavin transporter-3 (RFVT-3): role in functionality and cell biology

2019 ◽  
Vol 316 (6) ◽  
pp. C805-C814 ◽  
Author(s):  
Subrata Sabui ◽  
Veedamali S. Subramanian ◽  
Quang Pham ◽  
Hamid M. Said
Keyword(s):  
Cell Biology ◽  
Transmembrane Protein ◽  
Biological Significance ◽  
Intestinal Epithelial ◽  
Tnf Α ◽  
Epithelial Cell Lines ◽  
Confocal Images ◽  
Biological Aspects ◽  
Negative Controls ◽  
Function Cell

The apically localized riboflavin (RF) transporter-3 (RFVT-3) is involved in intestinal absorption of vitamin B2. Previous studies have characterized different physiological/biological aspects of the RFVT-3, but there is a lack of knowledge regarding possible existence of interacting partner(s) and consequence of interaction(s) on its function/cell biology. To address the latter, we performed yeast two-hybrid (Y2H) screening of a human colonic cDNA library and have identified transmembrane protein 237 (TMEM237) as a putative interactor with the human (h)RFVT-3; the interaction was further confirmed via “1-by-1” Y2H assay that involved appropriate positive and negative controls. TMEM237 was found to be highly expressed in human native intestine and in human intestinal epithelial cell lines; further, confocal images showed colocalization of the protein with hRFVT-3. The interaction between TMEM237 with hRFVT-3 in human intestinal epithelial HuTu-80 cells was established by coimmunoprecipitation. Expressing TMEM237 in HuTu-80 cells led to a significant induction in RF uptake, while its knockdown (with the use of gene-specific siRNA) led to a significant reduction in uptake. Transfecting TMEM237 into HuTu-80 cells also led to a marked enhancement in hRFVT-3 protein stability (reflected by an increase in the protein half-life). Interestingly, the level of expression of TMEM237 was found to be markedly reduced following treatment with TNF-α (a proinflammatory cytokine that inhibits intestinal RF uptake), while its expression was significantly upregulated following treatment with butyrate (an inducer of intestinal RF uptake). These findings identify TMEM237 as an interactor with the intestinal hRFVT-3 and show that the interaction has physiological/biological significance.

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