scholarly journals Multi-Tissue Characterization of GILZ Expression in Dendritic Cell Subsets at Steady State and in Inflammatory Contexts

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3153
Author(s):  
Molène Docq ◽  
Mathias Vétillard ◽  
Carmen Gallego ◽  
Agnieszka Jaracz-Ros ◽  
Françoise Mercier-Nomé ◽  
...  
Keyword(s):  
Steady State ◽  
Leucine Zipper ◽  
Tissue Characterization ◽  
Cell Function ◽  
Cell Subset ◽  
Skin Inflammation ◽  
Expression Levels ◽  
Multiparametric Flow Cytometry ◽  
Chronic Skin ◽  
Context Specific

Dendritic cells (DCs) are key players in the control of tolerance and immunity. Glucocorticoids (GCs) are known to regulate DC function by promoting their tolerogenic differentiation through the induction of inhibitory ligands, cytokines, and enzymes. The GC-induced effects in DCs were shown to critically depend on increased expression of the Glucocorticoid-Induced Leucine Zipper protein (GILZ). GILZ expression levels were further shown to control antigen-presenting cell function, as well as T-cell priming capacity of DCs. However, the pattern of GILZ expression in DC subsets across tissues remains poorly described, as well as the modulation of its expression levels in different pathological settings. To fill in this knowledge gap, we conducted an exhaustive analysis of GILZ relative expression levels in DC subsets from various tissues using multiparametric flow cytometry. This study was performed at steady state, in the context of acute as well as chronic skin inflammation, and in a model of cancer. Our results show the heterogeneity of GILZ expression among DC subsets as well as the complexity of its modulation, that varies in a cell subset- and context-specific manner. Considering the contribution of GILZ in the control of DC functions and its potential as an immune checkpoint in cancer settings, these results are of high relevance for optimal GILZ targeting in therapeutic strategies.

scholarly journals Sequestosome 1/p62 enhances chronic skin inflammation

2021 ◽  
Author(s):  
Supawadee Sukseree ◽  
Latifa Bakiri ◽  
Marta Palomo Irigoyen ◽  
Özge Uluçkan ◽  
Peter Petzelbauer ◽  
...  
Keyword(s):  
Skin Inflammation ◽  
Sequestosome 1 ◽  
Chronic Skin

scholarly journals Overexpression of β-Arrestins inhibits proliferation and motility in triple negative breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Saber Yari Bostanabad ◽  
Senem Noyan ◽  
Bala Gur Dedeoglu ◽  
Hakan Gurdal
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Function ◽  
Expression Profiles ◽  
Tissue Samples ◽  
Expression Levels ◽  
Cell Cycle Genes

Abstractβ-Arrestins (βArrs) are intracellular signal regulating proteins. Their expression level varies in some cancers and they have a significant impact on cancer cell function. In general, the significance of βArrs in cancer research comes from studies examining GPCR signalling. Given the diversity of different GPCR signals in cancer cell regulation, contradictory results are inevitable regarding the role of βArrs. Our approach examines the direct influence of βArrs on cellular function and gene expression profiles by changing their expression levels in breast cancer cells, MDA-MB-231 and MDA-MB-468. Reducing expression of βArr1 or βArr2 tended to increase cell proliferation and invasion whereas increasing their expression levels inhibited them. The overexpression of βArrs caused cell cycle S-phase arrest and differential expression of cell cycle genes, CDC45, BUB1, CCNB1, CCNB2, CDKN2C and reduced HER3, IGF-1R, and Snail. Regarding to the clinical relevance of our results, low expression levels of βArr1 were inversely correlated with CDC45, BUB1, CCNB1, and CCNB2 genes compared to normal tissue samples while positively correlated with poorer prognosis in breast tumours. These results indicate that βArr1 and βArr2 are significantly involved in cell cycle and anticancer signalling pathways through their influence on cell cycle genes and HER3, IGF-1R, and Snail in TNBC cells.

scholarly journals Oncogenic long intervening noncoding RNA Linc00284 promotes c-Met expression by sponging miR-27a in colorectal cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jun You ◽  
Jiayi Li ◽  
Chunlin Ke ◽  
Yanru Xiao ◽  
Chuanhui Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Noncoding Rna ◽  
Cell Function ◽  
In Vivo Studies ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Expression Levels ◽  
Clinical Biomarkers ◽  
Tumor Tissues

AbstractEmerging evidences suggest that long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and cancer progression. Here, the aim of this study is to investigate the biological function of long intervening noncoding RNA Linc00284 in colorectal cancer (CRC). The expression levels of Linc00284, miR-27a and c-Met were evaluated by qPCR and/or Western blotting. Immunohistochemistry was used to detect the expression of Ki67 and Phh3 in tumor tissues. The interaction between Linc00284, miR-27a and c-Met was validated by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell function experiments, including CCK-8, wound-healing and transwell invasion assays, were conducted. The in vivo studies were performed with the subcutaneous tumor xenograft mouse models. Our findings reveal that Linc00284 is upregulated in CRC tissues and colorectal cancer cell lines HCT116 and SW480 in comparison with corresponding para-carcinoma tissues and human fetal colonic mucosa cells FHC. High expression of Linc00284 in tumor tissues is associated with tumor metastasis and predicts a poor clinical outcome in CRC patients. Serum Linc00284 is increased, while miR-27a is decreased in CRC patients compared to healthy controls. ROC curve analysis indicates that serum Linc00284 and miR-27a produce the area under the curve (AUC) value of at 0.8151 and 0.7316 in patients with colorectal cancer compared to healthy individuals, respectively. Additionally, results in vitro and in vivo experiments suggest that Linc00284 silencing significantly suppresses CRC cell proliferation and/or invasion. Mechanistically, Linc00284 promotes c-Met expression by acting as miR-27a sponge, leading to the activation of downstream signaling pathways, thereby causing malignant phenotypes of CRC cells. Taken together, Linc00284 exhibits oncogenic function and the disturbance of Linc00284/miR-27a/c-Met regulatory axis contributes to CRC progression, providing new insight into the pathogenesis of colorectal cancer. Importantly, the expression levels of serum Linc00284 and miR-27a may serve as clinical biomarkers for CRC diagnosis.

MicroRNA-124 alleviates chronic skin inflammation in atopic eczema via suppressing innate immune responses in keratinocytes

2017 ◽  
Vol 319 ◽  
pp. 53-60 ◽  
Author(s):  
Zhibo Yang ◽  
Bijun Zeng ◽  
Chang Wang ◽  
Haizhen Wang ◽  
Pan Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Atopic Eczema ◽  
Skin Inflammation ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Microrna 124 ◽  
Chronic Skin

scholarly journals Inferring differential subcellular localisation in comparative spatial proteomics using BANDLE

2021 ◽  
Author(s):  
Oliver M. Crook ◽  
Colin T. R. Davies ◽  
Laurent Gatto ◽  
Paul D.W. Kirk ◽  
Kathryn S. Lilley
Keyword(s):  
Steady State ◽  
High Throughput ◽  
Statistical Power ◽  
Subcellular Localisation ◽  
Type I ◽  
Disease States ◽  
Proteomic Data ◽  
Rational Drug ◽  
Context Specific ◽  
Type Ii Errors

AbstractThe steady-state localisation of proteins provides vital insight into their function. These localisations are context specific with proteins translocating between different sub-cellular niches upon perturbation of the subcellular environment. Differential localisation provides a step towards mechanistic insight of subcellular protein dynamics. Aberrant localisation has been implicated in a number of pathologies, thus differential localisation may help characterise disease states and facilitate rational drug discovery by suggesting novel targets. High-accuracy high-throughput mass spectrometry-based methods now exist to map the steady-state localisation and re-localisation of proteins. Here, we propose a principled Bayesian approach, BANDLE, that uses these data to compute the probability that a protein differentially localises upon cellular perturbation, as well quantifying the uncertainty in these estimates. Furthermore, BANDLE allows information to be shared across spatial proteomics datasets to improve statistical power. Extensive simulation studies demonstrate that BANDLE reduces the number of both type I and type II errors compared to existing approaches. Application of BANDLE to datasets studying EGF stimulation and AP-4 dependent localisation recovers well studied translocations, using only two-thirds of the provided data. Moreover, we implicate TMEM199 with AP-4 dependent localisation. In an application to cytomegalovirus infection, we obtain novel insights into the rewiring of the host proteome. Integration of high-throughput transcriptomic and proteomic data, along with degradation assays, acetylation experiments and a cytomegalovirus interactome allows us to provide the functional context of these data.

scholarly journals ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvia D’Amico ◽  
Valerio D’Alicandro ◽  
Mirco Compagnone ◽  
Patrizia Tempora ◽  
Giusy Guida ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Human Tumor ◽  
Hla Class I ◽  
Class I ◽  
Pharmacological Inhibition ◽  
Mhc Class I Molecules

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

scholarly journals The Ly-49D Receptor Activates Murine Natural Killer Cells

1996 ◽  
Vol 184 (6) ◽  
pp. 2119-2128 ◽  
Author(s):  
L.H. Mason ◽  
S.K. Anderson ◽  
W.M. Yokoyama ◽  
H.R.C. Smith ◽  
R. Winkler-Pickett ◽  
...  
Keyword(s):  
Gene Family ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Cell Subset ◽  
Class I ◽  
Target Cells ◽  
Color Flow ◽  
Functional Capabilities

Proteins encoded by members of the Ly-49 gene family are predominantly expressed on murine natural killer (NK) cells. Several members of this gene family have been demonstrated to inhibit NK cell lysis upon recognizing their class I ligands on target cells. In this report, we present data supporting that not all Ly-49 proteins inhibit NK cell function. Our laboratory has generated and characterized a monoclonal antibody (mAb) (12A8) that can be used to recognize the Ly-49D subset of murine NK cells. Transfection of Cos-7 cells with known members of the Ly-49 gene family revealed that 12A8 recognizes Ly-49D, but also cross-reacts with the Ly-49A protein on B6 NK cells. In addition, 12A8 demonstrates reactivity by both immunoprecipitation and two-color flow cytometry analysis with an NK cell subset that is distinct from those expressing Ly-49A, C, or G2. An Ly-49D+ subset of NK cells that did not express Ly49A, C, and G2 was isolated and examined for their functional capabilities. Tumor targets and concanovalin A (ConA) lymphoblasts from a variety of H2 haplotypes were examined for their susceptibility to lysis by Ly-49D+ NK cells. None of the major histocompatibility complex class I–bearing targets inhibited lysis of Ly-49D+ NK cells. More importantly, we demonstrate that the addition of mAb 12A8 to Ly-49D+ NK cells can augment lysis of FcγR+ target cells in a reverse antibody-dependent cellular cytotoxicity–type assay and induces apoptosis in Ly49D+ NK cells. Furthermore, the cytoplasmic domain of Ly-49D does not contain the V/IxYxxL immunoreceptor tyrosine-based inhibitory motif found in Ly-49A, C, or G2 that has been characterized in the human p58 killer inhibitory receptors. Therefore, Ly-49D is the first member of the Ly-49 family characterized as transmitting positive signals to NK cells, rather than inhibiting NK cell function.

scholarly journals TWIST1 Preserves Hematopoietic Stem Cell Function Via Repression of Cacna1b Expression

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-12
Author(s):  
Nan Wang ◽  
Jing Yin ◽  
Na You ◽  
Dan Guo ◽  
Yangyang Zhao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Steady State ◽  
Calcium Channel ◽  
Cell Fate ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channel

The mitochondria of hematopoietic stem cell (HSC) play crucial roles in regulating cell fate and in preserving HSC functionality and survival. However, the mechanism underlying its regulation remain poorly understood. Here, we identify transcription factor TWIST1 as a novel regulator of HSC maintenance through modulating mitochondrial function. We demonstrate that Twist1 deletion results in a significantly decreased long-term HSC (LT-HSC) frequency, markedly reduced dormancy and self-renewal capacities and skewed myeloid differentiation in steady-state hematopoiesis. Twist1-deficient LT-HSC are more compromised in tolerance of irradiation and 5 fluorouracil-induced stresses, and exhibit typical phenotypes of senescence and higher levels of DNA damage and apoptosis. Mechanistically, Twist1 deficiency upregulates the expression of voltage-gated calcium channel Cacna1b in HSC, leading to noticeable increases in mitochondrial calcium levels, biogenesis, metabolic activity and reactive oxygen species production. Suppression of voltage-gated calcium channel by a calcium channel blocker largely rescues the phenotypic and functional defects in Twist1-deleted HSCs under both steady-state and stress conditions. Collectively, our data, for the first time, characterize TWIST1 as a critical regulator of HSC function acting through CACNA1B/Ca2+/mitochondria axis, and highlight the importance of Ca2+ in HSC maintenance. These observations provide new insights into the mechanisms for the control of HSC fate. Disclosures No relevant conflicts of interest to declare.

The VEGF-C/VEGFR3 signaling pathway contributes to resolving chronic skin inflammation by activating lymphatic vessel function

2014 ◽  
Vol 73 (2) ◽  
pp. 135-141 ◽  
Author(s):  
Asami Hagura ◽  
Jun Asai ◽  
Kazuichi Maruyama ◽  
Hideya Takenaka ◽  
Shigeru Kinoshita ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Lymphatic Vessel ◽  
Skin Inflammation ◽  
Chronic Skin

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3872-3879 ◽  
Author(s):  
Viola Hoffacker ◽  
Anja Schultz ◽  
James J. Tiesinga ◽  
Ralf Gold ◽  
Berthold Schalke ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cell Subset ◽  
Cell Repertoire ◽  
T Cell Subset ◽  
Functional Studies ◽  
Circulating T Cells

Abstract Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8+ phenotype. Moreover, it is primarily the proportion of circulating CD45RA+CD8+ T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma.

Sign in / Sign up

Export Citation Format

Share Document