Immune cells and Notch1 signaling appear to drive the epithelial to mesenchymal transition in the development of adenomyosis in mice

2021 ◽  
Author(s):  
M Bourdon ◽  
P Santulli ◽  
L Doridot ◽  
M Jeljeli ◽  
C Chêne ◽  
...  
Keyword(s):  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Immune Cell ◽  
Control Group ◽  
Aberrant Expression ◽  
M1 Macrophages ◽  
Mesenchymal Transition ◽  
Cell Markers ◽  
Notch1 Signaling

Abstract The epithelial to mesenchymal transition has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch signaling, that could promote this epithelial to mesenchymal transition. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated epithelial to mesenchymal transition in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30,60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5), and biomarkers of epithelial to mesenchymal transition (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T-cells) at Day 60. Conversely, expression of the Cd19 marker (B-cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for epithelial to mesenchymal transition were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and epithelial to mesenchymal transition markers in the early development of adenomyosis.

scholarly journals Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5625
Author(s):  
Rebecca Adams ◽  
Bernhard Moser ◽  
Sophia N. Karagiannis ◽  
Katie E. Lacy
Keyword(s):  
Immune Cells ◽  
Cutaneous Melanoma ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Metastatic Potential ◽  
Mesenchymal Transition ◽  
Emerging Therapies ◽  
Dense Cell ◽  
Chemokine Signalling ◽  
Melanoma Therapy

The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients.

Roles of Immune Cells in the Concurrence of Echinococcus Granulosus Infection and Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Aimaiti Yasen ◽  
Bo Ran ◽  
Maolin Wang ◽  
Guodong Lv ◽  
Renyong Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Echinococcus Granulosus ◽  
Immune Cells ◽  
Hepg2 Cells ◽  
Control Group ◽  
Cell Markers ◽  
Hepg2 Cell Lines

Abstract Background/aims: Immune cells are pivotal players in the immune responses against both parasitic infection and malignancies. Substantial evidence demonstrated that there may exist possible relationship between Echinococcus granulosus (E.granulosus) infection and hepatocellular carcinoma (HCC) development. Thus, this study aimed to observe crucial roles of immune cells in the formation of subcutaneous lesions after transplanting HepG2 cell lines with or without E.granulosus protoscoleces (PSCs).Methods: HepG2 cell lines were subcutaneously injected into nude mice in the control group. In the co-transplantation group, HepG2 cells were subcutaneously co-injected with high dosage of E.granulosus PSCs. From the 25th day of transplantation, volume of subcutaneous lesions was measured every four days, which were removed at the 37th day for further studies. Basic pathological and functional changes were observed. Moreover, expression of Ki67, Bal-2, Caspase3, α-smooth muscle actin (α-SMA), T cell markers (CD3, CD4, CD8), PD1/PD-L1, nature killer (NK) cell markers (CD16, CD56) were further detected by immunohistochemistry.Results: Subcutaneous lesions were gradually increased in volume and there occurred pathologically heterogeneous tumor cells, which were more significant in the co-transplantation group. Compared to the control group, expression of proliferation markers Ki67 and Bcl-2 was at higher levels in the co-transplantation group. Reversely, apoptotic marker Caspase3 was highly detected in the control group, suggesting promoting effects of E.granulosus PSCs on HCC development. Interestingly, subcutaneous lesions of the co-transplantation group were more functional in synthesizing and storing glycogen. Collagen and α-SMA+ cells were also at higher levels in the co-transplantation group than those in the control group. Most importantly, co-transplantation of HepG2 cells with E.granulosus PSCs led to significant increase in the expression of T cell markers (CD3, CD4 and CD8), immune inhibitory checkpoint PD1/PD-L1 and NK cells markers (CD16 and CD56). Conclusions: E.granulosus may have promoting effects on HCC development, which was closely associated with the immune responses of T cells and NK cells.

scholarly journals Activation of Notch1 signaling in podocytes by glucose-derived AGEs contributes to proteinuria

2020 ◽  
Vol 8 (1) ◽  
pp. e001203
Author(s):  
Rajkishor Nishad ◽  
Prajakta Meshram ◽  
Ashish Kumar Singh ◽  
G Bhanuprakash Reddy ◽  
Anil Kumar Pasupulati
Keyword(s):  
Notch Signaling ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Notch1 Signaling ◽  
Reverse Transcription Pcr ◽  
Filtration Barrier ◽  
Foot Process ◽  
Design And Methods

IntroductionAdvanced glycation end-products (AGEs) are implicated in the pathogenesis of diabetic nephropathy (DN). Previous studies have shown that AGEs contribute to glomerulosclerosis and proteinuria. Podocytes, terminally differentiated epithelial cells of the glomerulus and the critical component of the glomerular filtration barrier, express the receptor for AGEs (RAGE). Podocytes are susceptible to severe injury during DN. In this study, we investigated the mechanism by which AGEs contribute to podocyte injury.Research design and methodsGlucose-derived AGEs were prepared in vitro. Reactivation of Notch signaling was examined in AGE-treated human podocytes (in vitro) and glomeruli from AGE-injected mice (in vivo) by quantitative reverse transcription-PCR, western blot analysis, ELISA and immunohistochemical staining. Further, the effects of AGEs on epithelial to mesenchymal transition (EMT) of podocytes and expression of fibrotic markers were evaluated.ResultsUsing human podocytes and a mouse model, we demonstrated that AGEs activate Notch1 signaling in podocytes and provoke EMT. Inhibition of RAGE and Notch1 by FPS-ZM1 (N-Benzyl-4-chloro-N-cyclohexylbenzamide) and DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenyl glycine t-butylester), respectively, abrogates AGE-induced Notch activation and EMT. Inhibition of RAGE and Notch1 prevents AGE-induced glomerular fibrosis, thickening of the glomerular basement membrane, foot process effacement, and proteinuria. Furthermore, kidney biopsy sections from people with DN revealed the accumulation of AGEs in the glomerulus with elevated RAGE expression and activated Notch signaling.ConclusionThe data suggest that AGEs activate Notch signaling in the glomerular podocytes. Pharmacological inhibition of Notch signaling by DAPT ameliorates AGE-induced podocytopathy and fibrosis. Our observations suggest that AGE-induced Notch reactivation in mature podocytes could be a novel mechanism in glomerular disease and thus could represent a novel therapeutic target.

scholarly journals Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin

2007 ◽  
Vol 204 (12) ◽  
pp. 2935-2948 ◽  
Author(s):  
Kevin G. Leong ◽  
Kyle Niessen ◽  
Iva Kulic ◽  
Afshin Raouf ◽  
Connie Eaves ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Poor Prognosis ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Tumors ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Slug Expression ◽  
Tumor Growth And Metastasis ◽  
Notch Activation ◽  
E Cadherin

Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

scholarly journals Interleukin-8 Promotes Epithelial-to-Mesenchymal Transition via Downregulation of Mir-200 Family in Breast Cancer Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382097967
Author(s):  
Jin Zhang ◽  
Nan Shao ◽  
Xiaoyu Yang ◽  
Chuanbo Xie ◽  
Yawei Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Control Group ◽  
Mesenchymal Transition ◽  
Mcf 7

The microRNA-200 (miR-200) family has been reported to be vital for the inhibition of epithelial-to-mesenchymal transition (EMT) in tumor cells. The miR-200 family represents a complex multi-factorial regulatory network which has not been well described in breast cancer. This study aimed to clarify the underlying regulatory association between IL-8 and miR-200 family in the process of EMT in breast cancer cell. In estrogen-receptor (ER) positive breast cancer cell line MCF-7, IL-8 overexpression cells were performed by lentivirus transfection as endogenous regulation with additional exogenous IL-8 stimulation. Transient overexpressions of miR-200 family were performed after endogenous or exogenous IL-8 overexpression in MCF-7 cells. IL-8 knockdown cells were constructed via siRNA and shRNA transfection in triple negative breast cancer cell line MDA-MB-231. N-cadherin, vimentin and ZEB2 were down-regulated and E-cadherin was up-regulated in IL-8 knockdown group compared with control group. On the other hand, N-cadherin, vimentin and ZEB2 were up-regulated and E-cadherin was down-regulated in IL-8 overexpression group compared with control group. This indicated IL-8 promotes EMT in breast cancer cells. Transwell assay showed that IL-8 increased the migration and invasiveness of tumor cells. Furthermore, we performed transient overexpression of miR-200 family after endogenous or exogenous IL-8 overexpression in MCF-7 cells, which showed that the miR-200 family could inhibit EMT induced by IL-8. IL-8 promoted EMT via downregulation of miR-200 family expression in breast cancer cells and increases tumor cell migration and invasion.

scholarly journals An Assessment of Epithelial and Mesenchymal Phenotypes in Experimental and Clinical Pulmonary Fibrosis

2012 ◽  
Vol 2012 ◽  
pp. 1-11
Author(s):  
Rebecca Dunmore ◽  
Alan M. Carruthers ◽  
Matthew J. Bell ◽  
Huilan Zhang ◽  
Cory M. Hogaboam ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
A549 Cells ◽  
Mesenchymal Cell ◽  
Experimental Models ◽  
Epithelial Injury ◽  
Mesenchymal Transition ◽  
Cell Markers ◽  
Apoptotic Marker ◽  
Lung Biopsies

Epithelial injury has been implicated as a driving factor for the pathogenesis of idiopathic pulmonary fibrosis (IPF). In this study we investigated changes in epithelial and mesenchymal markers in experimental models of fibrosis and associated this with IPF. TGFβ1 induced an epithelial to mesenchymal transition (EMT) phenotype in A549 cells and normal human bronchial epithelial cells, with A549 cells exhibiting a more profound transition to a mesenchymal phenotype. TGFβ1 overexpression in the lungs of mice resulted in an early increase in mesenchymal cell markers and apoptotic genes that preceded collagen deposition, suggesting an early epithelial injury triggers the downstream fibrotic response. In contrast, bleomycin had a gradual increase in mesenchymal cell marker and a decrease in E-cadherin expression that correlated with collagen protein deposition. Finally, we compared normal healthy lung tissue with surgical lung biopsies from IPF patients and observed alterations in epithelial and mesenchymal cell markers, as well as an increase in the apoptotic marker GSK3β. Interestingly, the mesenchymal changes were more profound in rapidly progressive patients in comparison to IPF patients with slowing progressing disease. In summary, this study provides evidence of alterations in epithelial and mesenchymal markers in experimental models of lung fibrosis and how these findings are relevant to clinical disease.

scholarly journals FH535 Potentiation of Cigarette Smoke Condensate Cytotoxicity is Associated With Changes in β-Catenin and EGR-1 Signaling

2012 ◽  
Vol 31 (4) ◽  
pp. 380-389 ◽  
Author(s):  
William W. Polk
Keyword(s):  
Cigarette Smoke ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Protein Localization ◽  
Bronchial Epithelial Cell ◽  
Nuclear Accumulation ◽  
Epithelial Cell Line ◽  
Cigarette Smoke Condensate ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition

Cigarette smoke condensate (CSC) has been reported to elicit morphological and transcriptional changes that suggest epithelial-to-mesenchymal transition (EMT) in cultured bronchial epithelial cells. The transdifferentiation potential of acute and prolonged CSC exposure alone or in combination with the β-catenin inhibitor, FH535, was investigated in the bronchial epithelial cell line, BEAS-2B, through assessment of cell morphology, transcript expression, protein expression, and protein localization. Changes in morphology, β-catenin translocation, E-cadherin expression, metalloproteinase expression, and fibronectin could be demonstrated independent of molecular or physiological evidence of EMT. FH535 was shown to increase CSC-induced cytotoxicity and depress β-catenin expression. However, FH535 effects were not limited to the β-catenin pathway as it also blocked the expression of early growth responsive protein 1 (EGR-1) target genes, fibronectin and phosphatase and tensin homologue, without affecting EGR-1 nuclear accumulation.

scholarly journals Aberrant Expression of Long Non-Coding RNAs in Newly Diagnosed Type 2 Diabetes Indicates Potential Roles in Chronic Inflammation and Insulin Resistance

2017 ◽  
Vol 43 (6) ◽  
pp. 2367-2378 ◽  
Author(s):  
Xiaoli Wang ◽  
Xiangyun Chang ◽  
Peipei Zhang ◽  
Ling Fan ◽  
Ting Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Target Genes ◽  
Chinese Patients ◽  
Control Group ◽  
Newly Diagnosed ◽  
Aberrant Expression ◽  
Healthy Control ◽  
Non Coding Rnas

Background/Aims: Long non-coding RNAs (lncRNAs) have emerged as key players in several biological processes and complex diseases. The risk of type 2 diabetes (T2D) is determined by a combination of environmental factors and genetic susceptibility. The purpose of this study was to identify aberrant lncRNAs involved in T2D pathogenesis. Methods: Microarray analysis was performed using whole blood samples from patients newly diagnosed with T2D and healthy controls. Pathway and Gene Ontology (GO) analyses were utilized to annotate the target genes. Coding non-coding co-expression (CNC) analysis was performed to construct a co-expression network. Results: We found 55 lncRNAs and 202 mRNAs were differentially expressed in the T2D group compared to the healthy control group. Pathway and GO analyses demonstrated that dysregulated mRNAs were mainly associated with immune regulation, inflammation, and insulin resistance, whereas CNC analysis identified 10 pairs of co-expressed lncRNA-mRNAs in our patient cohort (R > 0.99). Furthermore, expression of the top three upregulated lncRNAs in the T2D group was correlated with measures of glycometabolism (P < 0.05). Conclusion: This study identified aberrantly expressed lncRNAs and mRNAs in Han Chinese patients with T2D, and demonstrated that dysregulated lncRNAs may have roles in T2D pathogenesis through regulation of inflammation and insulin resistance.

scholarly journals Identification of Potential ceRNA Network and Patterns of Immune Cell Infiltration in Systemic Sclerosis-Associated Interstitial Lung Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiuhong Wu ◽  
Yang Liu ◽  
Yan Xie ◽  
Shixiong Wei ◽  
Yi Liu
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Immune Cells ◽  
Regulatory Network ◽  
Target Genes ◽  
Immune Cell ◽  
Differentially Expressed ◽  
Immune Cell Infiltration ◽  
Overlapping Genes

PurposeSystemic sclerosis-associated interstitial lung disease (SSc-ILD) is one of the most severe complications of systemic sclerosis (SSc) and is the leading cause of SSc-related deaths. However, the precise pathogenesis of pulmonary fibrosis in SSc-ILD remains unknown. This study aimed to evaluate the competing endogenous RNA (ceRNA) regulatory network and immune cell infiltration patterns in SSc-ILD.MethodsOne microRNA (miRNA) and three messenger RNA (mRNA) microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. Then, the differentially expressed miRNAs (DEmiRs) and mRNAs (DEMs) between SSc-ILD patients and normal controls were identified, respectively, followed by the prediction of the target genes and target lncRNAs of DEmiRs. The overlapping genes between DEmiRs target genes and DEMs were identified as core mRNAs to construct the ceRNA network. In addition, the “Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT)” algorithm was used to analyze the composition of infiltrating immune cells in lung tissues of SSc-ILD patients and controls, and differentially expressed immune cells were recognized. The correlation between immune cells and core mRNAs was evaluated by Pearson correlation analysis.ResultsTotally, 42 SSc-ILD lung tissues and 18 normal lung tissues were included in this study. We identified 35 DEmiRs and 142 DEMs and predicted 1,265 target genes of DEmiRs. Then, 9 core mRNAs related to SSc-ILD were recognized, which were the overlapping genes between DEmiRs target genes and DEMs. Meanwhile, 9 DEmiRs related to core mRNAs were identified reversely, and their target lncRNAs were predicted. In total, 9 DEmiRs, 9 core mRNAs, and 51 predicted lncRNAs were integrated to construct the ceRNA regulatory network of SSc-ILD. In addition, 9 types of immune cells were differentially expressed in lung tissues between SSc-ILD patients and controls. Some core mRNAs, such as COL1A1, FOS, and EDN1, were positively or negatively correlated with the number of infiltrating immune cells.ConclusionThis is the first comprehensive study to construct the potential ceRNA regulatory network and analyze the composition of infiltrating immune cells in lung tissues of SSc-ILD patients, which improves our understanding of the pathogenesis of SSc-ILD.

scholarly journals Simulated bacterial infection disrupts the circadian fluctuation of immune cells in wrinkle-lipped bats (Chaerephon plicatus)

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3570 ◽  
Author(s):  
Philipp Weise ◽  
Gábor A. Czirják ◽  
Oliver Lindecke ◽  
Sara Bumrungsri ◽  
Christian C. Voigt
Keyword(s):  
Bacterial Infection ◽  
Immune Cells ◽  
Immune Cell ◽  
Experimental Treatment ◽  
Cell Types ◽  
Diurnal Fluctuation ◽  
Control Group ◽  
Carrier Liquid ◽  
Cell Counts ◽  
Body Mass Changes

BackgroundLeukocyte concentrations follow a circadian pattern in mammals, with elevated values at times of potential contact with pathogens and parasites. We hypothesized that this pattern is disturbed after an immune challenge.MethodsIn Thailand, we captured wrinkle-lipped bats (Chaerephon plicatus), when they returned to their colony at dawn. We challenged half of the animals (experimental group) with bacterial lipopolysaccharides and treated the others only with the carrier liquid (control group). We then compared body mass changes and differences in circulating immune cell counts at 8 h post-treatment.ResultsIn experimental animals, we observed an increase in total leukocyte and neutrophil numbers of 17% and 95%, respectively. In control animals, concentrations of leukocytes decreased by 44% and those of neutrophils remained constant. Experimental treatment had no effect on lymphocytes, yet changes in eosinophil numbers were explained by sex. Eosinophils decreased by 66% in females and by 62% in males. Basophils and monocytes were rarest among all observed cell types and analysis was either impossible because of low numbers or yielded no significant effects, respectively.DiscussionOur findings show that a simulated bacterial infection triggered a neutrophil-associated immune response in wrinkle-lipped bats, indicating a disruption of the diurnal fluctuation of immune cells. Our study suggests that bats exhibit circadian rhythms in immune cell counts. The magnitude of these fluctuations may vary across species according to specific-specific infection risks associated with colony sizes or specific roosting habits.

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