scholarly journals Molecular profiling demonstrates modulation of immune cell function and matrix remodeling during luteal rescue†

2019 ◽  
Vol 100 (6) ◽  
pp. 1581-1596 ◽  
Author(s):  
Camilla K Hughes ◽  
Samar W Maalouf ◽  
Wan-Sheng Liu ◽  
Joy L Pate
Keyword(s):  
Extracellular Matrix ◽  
Corpus Luteum ◽  
Cell Function ◽  
Immune Cell ◽  
Cell Receptor ◽  
Cytokine Signaling ◽  
Matrix Remodeling ◽  
Proteomic Profiling ◽  
Interferon Tau ◽  
In Pregnancy

Abstract The corpus luteum (CL) is essential for maintenance of pregnancy in all mammals and luteal rescue, which occurs around day 16–19 in the cow, is necessary to maintain luteal progesterone production. Transcriptomic and proteomic profiling were performed to compare the day 17 bovine CL of the estrous cycle and pregnancy. Among mRNA and proteins measured, 140 differentially abundant mRNA and 24 differentially abundant proteins were identified. Pathway analysis was performed using four programs. Modulated pathways included T cell receptor signaling, vascular stability, cytokine signaling, and extracellular matrix remodeling. Two mRNA that were less in pregnancy were regulated by prostaglandin F2A in culture, while two mRNA that were greater in pregnancy were regulated by interferon tau. To identify mRNA that could be critical regulators of luteal fate, the mRNA that were differentially abundant during early pregnancy were compared to mRNA that were differentially abundant during luteal regression. Eight mRNA were common to both datasets, including mRNA related to regulation of steroidogenesis and gene transcription. A subset of differentially abundant mRNA and proteins, including those associated with extracellular matrix functions, were predicted targets of differentially abundant microRNA (miRNA). Integration of miRNA and protein data, using miRPath, revealed pathways such as extracellular matrix–receptor interactions, abundance of glutathione, and cellular metabolism and energy balance. Overall, this study has provided a comprehensive profile of molecular changes in the corpus luteum during maternal recognition of pregnancy and has indicated that some of these functions may be miRNA-regulated.

Differential fractal dimension is associated with extracellular matrix remodeling in developing bovine corpus luteum

2019 ◽  
Vol 516 (3) ◽  
pp. 888-893 ◽  
Author(s):  
Paola Francini Fávero ◽  
Victor Augusto Vieira de Lima ◽  
Priscila Helena dos Santos ◽  
Ana Paula Marques Andrade ◽  
Leonardo Oliveira Mendes ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Fractal Dimension ◽  
Corpus Luteum ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Bovine Corpus Luteum

scholarly journals Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity

2017 ◽  
Vol 214 (3) ◽  
pp. 609-622 ◽  
Author(s):  
Andrew G. Levine ◽  
Saskia Hemmers ◽  
Antonio P. Baptista ◽  
Michail Schizas ◽  
Mehlika B. Faire ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Gene Expression Signature ◽  
Cell Receptor ◽  
Tcr Repertoire ◽  
Helper Cell Type ◽  
Self Antigens

The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR-mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity. An induced switch of the T reg cell TCR repertoire to a random repertoire also preserved, albeit to a limited degree, the ability to suppress lymphadenopathy and T helper cell type 2 activation. At the same time, these perturbations of the T reg cell TCR repertoire led to marked immune cell activation, tissue inflammation, and an ultimately severe autoimmunity, indicating the importance of diversity and specificity for optimal T reg cell function.

scholarly journals Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells

Vaccines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1294
Author(s):  
Richard M. Powell ◽  
Marlies J. W. Peeters ◽  
Anne Rahbech ◽  
Pia Aehnlich ◽  
Tina Seremet ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tyrosine Kinases ◽  
Cell Function ◽  
Immune Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Induce Cell Cycle Arrest

There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8+ T cell function. Using ex vivo T cell receptor (TCR)-activated CD8+ T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8+ T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8+ T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses.

scholarly journals 694 NC410 is a novel immunomedicine for the treatment of solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A736-A736
Author(s):  
Linjie Tian ◽  
M Ines Pascoal Ramos ◽  
Emma de Ruiter ◽  
Ana Paucarmayta ◽  
Eline Elshof ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
Cancer Therapeutics ◽  
Effector Function ◽  
Local Tumor ◽  
Tumor Microenvironments ◽  
Tumor Environment

BackgroundAbnormalities in the extracellular matrix of tumor microenvironments support tumor progression, lead to immune dysfunction, and provide a target for cancer therapeutics. Collagens are a primary component of the extracellular matrix. Abnormal levels of collagen and of the collagen-domain containing complement component 1q (C1q) in tumor microenvironments has been proposed to disrupt anti-tumor immunity. LAIR-1 is an adhesion molecule and inhibitory receptor expressed on the cell surface of several immune cell subsets. LAIR-1 binding to collagen-like domains present in collagens and C1q inhibit immune cell function. LAIR-2 is a soluble homolog of LAIR-1 that binds to and outcompetes LAIR-1 binding to collagens and C1q and serves as a natural decoy to promote immune function.MethodsTaking advantage of a natural decoy system, we designed a protein biologic, NC410, composed of LAIR-2 fused with a functional IgG1 Fc domain to target collagen-rich tumors and promote immune activation, infiltration and effector function.ResultsNC410 has increased avidity due to Fc mediated dimerization, and blocks LAIR-1 interactions with ligands, and LAIR-1 signaling. In vivo administration of NC410 in humanized tumor models reduced tumor growth in a dose dependent fashion. NC410 increased the numbers of infiltrating human CD8+ and CD4+ T cells in the tumor, which is associated with increased levels of chemokines in the local tumor environment. Effector function was also enhanced, as denoted by increased levels of IFN-gamma and Granzyme B in the local tumor environment. In addition, NC410 increased specific collagen degradative products in the serum of humanized tumor-bearing mice, suggesting NC410 may promote tumor microenvironment remodeling and immune accessibility to further promote anti-tumor immunity.ConclusionsThese data support NC410 as a novel therapeutic for targeting collagen-rich tumors and enabling normalization of the tumor-immune microenvironment. FIH studies have recently been initiated with NC410.

Consequences of Extracellular Matrix Remodeling in Headway and Metastasis of Cancer along with Novel Immunotherapies: A Great Promise for Future Endeavor

2021 ◽  
Vol 21 ◽  
Author(s):  
Suman Kumar Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Extracellular Matrix ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Control Cell ◽  
Tumor Stroma ◽  
Great Promise ◽  
Matrix Remodeling ◽  
Extrinsic Factors ◽  
Ecm Remodeling ◽  
Normal Tissues

: Tissues are progressively molded by bidirectional correspondence between denizen cells and extracellular matrix (ECM) via cell-matrix connections along with ECM remodeling. The composition and association of ECM are spatiotemporally directed to control cell conduct and differentiation; however, dysregulation of ECM dynamics prompts the development of diseases, for example, cancer. Emerging information demonstrates that hypoxia may have decisive roles in metastasis. In addition, the sprawling nature of neoplastic cells and chaotic angiogenesis are increasingly influencing microcirculation as well as altering the concentration of oxygen. In various regions of the tumor microenvironment, hypoxia, an essential player in the multistep phase of cancer metastasis, is necessary. Hypoxia can be turned into an advantage for selective cancer therapy because it is much more severe in tumors than in normal tissues. Cellular matrix gives signaling cues that control cell behavior and organize cells' elements in tissue development and homeostasis. The interplay between intrinsic factors of cancer cells themselves, including their genotype and signaling networks, and extrinsic factors of tumor stroma, for example, ECM and ECM remodeling, together decide the destiny and behavior of tumor cells. Tumor matrix encourages the development, endurance, and invasion of neoplastic and immune cell activities to drive metastasis and debilitate treatment. Incipient evidence recommends essential parts of tumor ECM segments and their remodeling in controlling each progression of the cancer-immunity cycle. Scientists have discovered that tumor matrix dynamics as well as matrix remodeling in perspective to anti-tumor immune reactions are especially important for matrix-based biomarkers recognition and followed by immunotherapy and targeting specific drugs.

scholarly journals A Lipocalin-Derived Peptide Modulating Fibroblasts and Extracellular Matrix Proteins

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Linda Christian Carrijo-Carvalho ◽  
Durvanei A. Maria ◽  
Janaina S. Ventura ◽  
Kátia L. P. Morais ◽  
Robson L. Melo ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Cytokine Signaling ◽  
Sequence Motif ◽  
Matrix Remodeling ◽  
Ki 67 ◽  
Proinflammatory Mediators ◽  
Lonomia Obliqua

Lipocalin family members have been implicated in development, regeneration, and pathological processes, but their roles are unclear. Interestingly, these proteins are found abundant in the venom of theLonomia obliquacaterpillar. Lipocalins areβ-barrel proteins, which have three conserved motifs in their amino acid sequence. One of these motifs was shown to be a sequence signature involved in cell modulation. The aim of this study is to investigate the effects of a synthetic peptide comprising the lipocalin sequence motif in fibroblasts. This peptide suppressed caspase 3 activity and upregulated Bcl-2 and Ki-67, but did not interfere with GPCR calcium mobilization. Fibroblast responses also involved increased expression of proinflammatory mediators. Increase of extracellular matrix proteins, such as collagen, fibronectin, and tenascin, was observed. Increase in collagen content was also observed in vivo. Results indicate that modulation effects displayed by lipocalins through this sequence motif involve cell survival, extracellular matrix remodeling, and cytokine signaling. Such effects can be related to the lipocalin roles in disease, development, and tissue repair.

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

2015 ◽  
Vol 309 (8) ◽  
pp. E691-E714 ◽  
Author(s):  
Amaia Rodríguez ◽  
Silvia Ezquerro ◽  
Leire Méndez-Giménez ◽  
Sara Becerril ◽  
Gema Frühbeck
Keyword(s):  
Extracellular Matrix ◽  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Glucose Disposal ◽  
Cytokine Signaling ◽  
Matrix Remodeling ◽  
Nonalcoholic Fatty Liver ◽  
Brown Adipose ◽  
Wide Range ◽  
Beige Fat

Adipose tissue constitutes an extremely active endocrine organ with a network of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a huge variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins, and vasoactive factors, collectively termed adipokines. Obesity is associated with adipose tissue dysfunction leading to the onset of several pathologies including type 2 diabetes, dyslipidemia, nonalcoholic fatty liver, or hypertension, among others. The mechanisms underlying the development of obesity and its associated comorbidities include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. Recently, the potential role of brown and beige adipose tissue in the protection against obesity has been also recognized. In contrast to white adipocytes, which store energy in the form of fat, brown and beige fat cells display energy-dissipating capacity through the promotion of triacylglycerol clearance, glucose disposal, and generation of heat for thermogenesis. Identification of the morphological and molecular changes in white, beige, and brown adipose tissue during weight gain is of utmost relevance for the identification of pharmacological targets for the treatment of obesity and its associated metabolic diseases.

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