scholarly journals PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Juliane Obst ◽  
Hazel L. Hall-Roberts ◽  
Thomas B. Smith ◽  
Mira Kreuzer ◽  
Lorenza Magno ◽  
...  
Keyword(s):  
Calcium Release ◽  
Cell Function ◽  
Immune Cell ◽  
Induced Pluripotent Stem Cell ◽  
Myeloid Cell ◽  
Cellular Adhesion ◽  
Calcium Flux ◽  
Surface Receptors ◽  
And Migration

AbstractHuman genetic studies have linked rare coding variants in microglial genes, such as TREM2, and more recently PLCG2 to Alzheimer’s disease (AD) pathology. The P522R variant in PLCG2 has been shown to confer protection for AD and to result in a subtle increase in enzymatic activity. PLCγ2 is a key component of intracellular signal transduction networks and induces Ca2+ signals downstream of many myeloid cell surface receptors, including TREM2. To explore the relationship between PLCγ2 and TREM2 and the role of PLCγ2 in regulating immune cell function, we generated human induced pluripotent stem cell (iPSC)- derived macrophages from isogenic lines with homozygous PLCG2 knockout (Ko). Stimulating TREM2 signalling using a polyclonal antibody revealed a complete lack of calcium flux and IP1 accumulation in PLCγ2 Ko cells, demonstrating a non-redundant role of PLCγ2 in calcium release downstream of TREM2. Loss of PLCγ2 led to broad changes in expression of several macrophage surface markers and phenotype, including reduced phagocytic activity and survival, while LPS-induced secretion of the inflammatory cytokines TNFα and IL-6 was unaffected. We identified additional deficits in PLCγ2- deficient cells that compromised cellular adhesion and migration. Thus, PLCγ2 is key in enabling divergent cellular functions and might be a promising target to increase beneficial microglial functions.

Immunometabolism in bladder cancer microenvironment

2022 ◽  
Vol 22 ◽  
Author(s):  
Mohammad Javad Fattahi ◽  
Mohammad Reza Haghshenas ◽  
Abbas Ghaderi
Keyword(s):  
Bladder Cancer ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Metabolic Reprogramming ◽  
Immune Cell Function ◽  
Complex Interactions ◽  
Metabolite Accumulation ◽  
And Migration

Abstract: The initiation and progression of bladder cancer (BC), is dependent on its tumor microenvironment (TME). On the other hand, cancer cells shape and train TME to support their development, respond to treatment and migration in an organism. Immune cells exert key roles in the BC microenvironment and have complex interactions with BC cells. These complicated interplays result in metabolic competition in the TME leading to nutrient deprivation, acidosis, hypoxia and metabolite accumulation, which impair immune cell function. Recent studies have demonstrated that immune cells functions are closely correlated with their metabolism. Immunometabolism describes the functional metabolic alterations that take place within immune cells and the role of these cells in directing metabolism and immune response in tissues or diseases such as cancer. Some molecules and their metabolites in the TME including glucose, fatty acids and amino acids can regulate the phenotype, function and metabolism of immune cells. Hence, here we describe some recent advances in immunometabolism and relate them to BC progression. A profound understanding of the metabolic reprogramming of BC cells and immune cells in the TME will offer novel opportunities for targeted therapies in future.

scholarly journals Deciphering the Role of Endolysosomal Ca2+ Channels in Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Abeer F. Alharbi ◽  
John Parrington
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Innate And Adaptive Immunity ◽  
Adaptive Immune ◽  
Physiological Processes ◽  
And Migration ◽  
Ca2 Channels

The role of endolysosomal Ca2+ signalling in immunity has been a subject of increasing interest in recent years. Here, we discuss evolving knowledge relating to the contribution of endolysosomal Ca2+ channels that include TPCs, TRPMLs, and P2X4R in physiological processes related to innate and adaptive immunity—including phagocytosis, inflammation, cytokine/chemokine release, dendritic, natural killer, and T cell activation and migration—and we underscore the paucity of clinical studies in this field. Emerging biomedical and translational data have led to important new insights into the critical roles of these channels in immune cell function and the regulation of innate and adaptive immune responses. The evolving immunological significance of endolysosomal Ca2+ signalling warrants further investigations to better characterize the roles of these channels in immunity in order to expand our knowledge about the pathology of inflammatory and autoimmune diseases and develop endolysosomal Ca2+ channels as viable biomarkers and therapeutic and preventive targets for remodelling the immune response.

scholarly journals miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

2011 ◽  
Vol 208 (6) ◽  
pp. 1189-1201 ◽  
Author(s):  
Mark P. Boldin ◽  
Konstantin D. Taganov ◽  
Dinesh S. Rao ◽  
Lili Yang ◽  
Jimmy L. Zhao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Genetically Engineered ◽  
Biological Processes ◽  
Targeted Deletion ◽  
Genetically Engineered Mice ◽  
Immune Defects ◽  
Molecular Brake

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

scholarly journals Nonneuronal Cholinergic System in Breast Tumors and Dendritic Cells: Does It Improve or Worsen the Response to Tumor?

2013 ◽  
Vol 2013 ◽  
pp. 1-12
Author(s):  
Marisa Vulcano ◽  
María Gabriela Lombardi ◽  
María Elena Sales
Keyword(s):  
Dendritic Cells ◽  
Cholinergic System ◽  
Parasympathetic Nervous System ◽  
Immune Cell ◽  
Breast Tumors ◽  
Cell Types ◽  
Cellular Functions ◽  
And Migration ◽  
And Function

Besides being the main neurotransmitter in the parasympathetic nervous system, acetylcholine (ACh) can act as a signaling molecule in nonneuronal tissues. For this reason, ACh and the enzymes that synthesize and degrade it (choline acetyltransferase and acetylcholinesterase) as well as muscarinic (mAChRs) and nicotinic receptors conform the non-neuronal cholinergic system (nNCS). It has been reported that nNCS regulates basal cellular functions including survival, proliferation, adhesion, and migration. Moreover, nNCS is broadly expressed in tumors and in different components of the immune system. In this review, we summarize the role of nNCS in tumors and in different immune cell types focusing on the expression and function of mAChRs in breast tumors and dendritic cells (DCs) and discussing the role of DCs in breast cancer.

scholarly journals Reduction of leucocyte cell surface disulfide bonds during immune activation is dynamic as revealed by a quantitative proteomics workflow (SH-IQ)

Open Biology ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 180079
Author(s):  
Monika Stegmann ◽  
A. Neil Barclay ◽  
Clive Metcalfe
Keyword(s):  
Immune System ◽  
Cell Surface ◽  
Immune Activation ◽  
Disulfide Bonds ◽  
Cell Function ◽  
Immune Cell ◽  
Surface Proteins ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Pathogen Clearance

Communication through cell surface receptors is crucial for maintaining immune homeostasis, coordinating the immune response and pathogen clearance. This is dependent on the interaction of cell surface receptors with their ligands and requires functionally active conformational states. Thus, immune cell function can be controlled by modulating the structure of either the receptor or the ligand. Reductive cleavage of labile disulfide bonds can mediate such an allosteric change, resulting in modulation of the immune system by a hitherto little studied mechanism. Identifying proteins with labile disulfide bonds and determining the extent of reduction is crucial in elucidating the functional result of reduction. We describe a mass spectrometry-based method—thiol identification and quantitation (SH-IQ)—to identify, quantify and monitor such reduction of labile disulfide bonds in primary cells during immune activation. These results provide the first insight into the extent and dynamics of labile disulfide bond reduction in leucocyte cell surface proteins upon immune activation. We show that this process is thiol oxidoreductase-dependent and mainly affects activatory (e.g. CD132, SLAMF1) and adhesion (CD44, ICAM1) molecules, suggesting a mechanism to prevent over-activation of the immune system and excessive accumulation of leucocytes at sites of inflammation.

Role of Integrin αvβ3 in Vascular Biology

1998 ◽  
Vol 80 (11) ◽  
pp. 726-734 ◽  
Author(s):  
Tatiana Byzova ◽  
Ramin Rabbani ◽  
Stanley D’Souza ◽  
Edward Plow
Keyword(s):  
Cell Biology ◽  
Cell Function ◽  
Thrombus Formation ◽  
Cellular Adhesion ◽  
Vascular Cells ◽  
Functional Responses ◽  
Adhesive Properties ◽  
Adhesion Receptors ◽  
Vascular Cell

IntroductionA defining characteristic of vascular cells is their adhesive status. The predominant cells of the blood vessel, endothelial cells (EC) and smooth muscle cells (SMC), are normally adherent but can be induced to migrate in response to vascular injury and angiogenic stimuli. The circulating blood cells are ordinarily nonadhesive but can rapidly acquire an adhesive phenotype in response to physiologic and pathophysiologic stimuli. As prime examples, platelets become adherent to the subendothelial matrix and to one another during thrombus formation, and leukocytes first adhere to EC and then transmigrate during the inflammatory response. At a molecular level, the adhesive properties of the vascular cells are determined by the adhesion receptors on their cell-surface and the functional state of these receptors. To match the variety of requisite cellular adhesive reactions, the repertoire of adhesion receptors expressed by vascular cells is broad. Multiple representatives of the immunoglobulin-like, the selectin, the cadherin and the integrin families of adhesion receptors are present on and have been implicated in the functions of the vascular cells. The importance of these adhesion receptors in vascular cell function is underscored by the severe pathogenetic consequences of their congenital deficiencies, such as in Glanzmann’s thrombasthenia, LAD (Leucocyte Adhesion deficiency) I and LAD II (1-3).The integrins are the largest and most broadly distributed of the families of cellular adhesion receptors. Of the integrins, αvβ3, originally identified as the vitronectin receptor, is particularly widely distributed. It is expressed at variable density on many types of vascular cells. Obviously, the adhesive properties of a cell are determined by its full repertoire of adhesion receptors. As an example, the adhesion of EC to fibrinogen/fibrin is mediated by no fewer than five receptors. Nevertheless, it is possible to dissect out the contributions of individual adhesion receptors, and αvβ3 has been implicated in many functional responses of vascular cells. This review focusses upon the role of αvβ3 in vascular cell biology. Other contributions of this multifunctional receptor, such as its role in neoplastic growth and invasion and in osteoclast-mediated bone resorption, are beyond the scope of this article and have been reviewed elsewhere (4, 5).

scholarly journals Integrins as architects of cell behavior

2016 ◽  
Vol 27 (19) ◽  
pp. 2885-2888 ◽  
Author(s):  
Charles H. Streuli
Keyword(s):  
Extracellular Matrix ◽  
Mammary Gland ◽  
Cell Surface ◽  
Cell Function ◽  
External Environment ◽  
Cell Behavior ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Mammary Gland Differentiation

Integrins are cell surface receptors that bind cells to their physical external environment, linking the extracellular matrix to cell function. They are essential in the biology of all animals. In the late 1980s, we discovered that integrins are required for the ability of breast epithelia to do what they are programmed to do, which is to differentiate and make milk. Since then, integrins have been shown to control most other aspects of phenotype: to stay alive, to divide, and to move about. Integrins also provide part of the mechanism that allows cells to form tissues. Here I discuss how we discovered that integrins control mammary gland differentiation and explore the role of integrins as central architects of other aspects of cell behavior.

scholarly journals Impact of Exercise on Immunometabolism in Multiple Sclerosis

2020 ◽  
Vol 9 (9) ◽  
pp. 3038 ◽  
Author(s):  
Remsha Afzal ◽  
Jennifer K Dowling ◽  
Claire E McCoy
Keyword(s):  
Multiple Sclerosis ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Benefits ◽  
Demyelinating Lesions ◽  
Inflammatory State ◽  
Autoimmune Condition ◽  
The Central Nervous System ◽  
Axonal Degradation

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

Human pregnancy: the role of chemokine networks at the fetal–maternal interface

2004 ◽  
Vol 6 (11) ◽  
pp. 1-14 ◽  
Author(s):  
Kristy Red-Horse ◽  
Penelope M. Drake ◽  
Susan J. Fisher
Keyword(s):  
Chemokine Receptors ◽  
Immune Cell ◽  
Leukocyte Trafficking ◽  
Placental Development ◽  
Effector Cells ◽  
Chemokine Expression ◽  
Multifunctional Molecules ◽  
And Migration ◽  
The Relationship

Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. Similar events occur in pregnancy during development of the fetal–maternal interface, where there is extensive leukocyte trafficking and tissue morphogenesis, and this is accompanied by abundant chemokine expression. The relationship between chemokines, leukocytes and placental development is beginning to be delineated. During pregnancy a specialised population of maternal leukocytes infiltrates the implantation site. These leukocytes are thought to sustain the delicate balance between protecting the developing embryo/fetus and tolerating its hemiallogeneic tissues. A network of chemokine expression by both fetal and maternal components in the pregnant uterus functions in establishing this leukocyte population. Intriguingly, experiments investigating immune cell recruitment revealed the additional possibility that chemokines influence aspects of placental development. Specifically, cytotrophoblasts, the effector cells of the placenta, express chemokine receptors that can bind ligands found at key locations, implicating chemokines as regulators of cytotrophoblast differentiation and migration. Thus, as in other systems, at the fetal–maternal interface chemokines might regulate multiple functions.

The gene coding for secreted phosphoprotein1/osteopontin is the most overexpressed gene in cholangiocarcinoma—detected by oligonucleotide arrays and LightCycler analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10036-10036
Author(s):  
H. G. Hass ◽  
J. Jobst ◽  
O. Nehls ◽  
A. Frilling ◽  
J. T. Hartmann ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Cell Phenotype ◽  
Oligonucleotide Arrays ◽  
Surface Receptors ◽  
Malignant Liver ◽  
And Control

10036 Background: Cholangiocarcinomas (CCC) are the second most common primary hepatic malignancy with a still poor prognosis and arise from biliary epithelia or cholangiocytes. Until now, less is known about the molecular pathways leeding to CCC. Methods: Oligonucleotide arrays were used to analyze gene expression profiles of 8 intrahepatic CCCs. After isolation of tRNA and transcription into cDNA, biotin-labelled cRNA probes were hybridized to GeneArrays (Affymetrix U 133A) containing probes of more than 22.000 genes/ESTs. For two-dimensional cluster analysis we used special software programs (Genexplore, GeneSpring). Dysregulated genes were determined by presence in more than 70% and a 2-fold change in relation to the corresponding non-malignant liver tissue. Lightcycler analysis were performed to validate the expression datas of dysregulated genes. Results: A total of 694 dysregulated genes (330 up-/364 down-regulated, compared with corresponding non-malignant tissue) were detected. As the gene with the highest and most consistent upregulation we were able to identify osteopontin (OPN) with an average 5-fold overexpression in all CCC tissues. OPN is an acidic phosphoprotein that is secreted by osteoblasts, macrophages and many other cell types and binds to a variety of cell surface receptors (integrins/CD44). OPN is multifunctional, with activities in cell migration, regulation of bone metabolism, immune cell function and control of tumor cell phenotype. Elevated OPN levels were seen in different tumors but until now no data exist about the expression in CCCs. As one possible interaction in human carcinogenesis, OPN has recently been shown to be a novel substrate for some MMPs, which play an importand role in tumor invasion and metastasis. Conclusions: This is the first report about an overexpression of OPN in CCC and our data indicate an important role in cholangiocarcinogenesis. Further studies are needed to illucidate the moleculargenetic mechanisms of OPN interactions in CCC. No significant financial relationships to disclose.

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