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JCI Insight Aug 2021The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN...
The stimulator of IFN genes (STING) protein senses cyclic dinucleotides released in response to double-stranded DNA and functions as an adaptor molecule for type I IFN (IFNI) signaling by activating IFNI-stimulated genes (ISG). We found impaired T cell infiltration into the peritoneum in response to TNF-α in global and EC-specific STING-/- mice and discovered that T cell transendothelial migration (TEM) across mouse and human endothelial cells (EC) deficient in STING was strikingly reduced compared with control EC, whereas T cell adhesion was not impaired. STING-/- T cells showed no defect in TEM or adhesion to EC, or immobilized endothelial cell-expressed molecules ICAM1 and VCAM1, compared with WT T cells. Mechanistically, CXCL10, an ISG and a chemoattractant for T cells, was dramatically reduced in TNF-α-stimulated STING-/- EC, and genetic loss or pharmacologic antagonisms of IFNI receptor (IFNAR) pathway reduced T cell TEM. Our data demonstrate a central role for EC-STING during T cell TEM that is dependent on the ISG CXCL10 and on IFNI/IFNAR signaling.
Topics: Animals; Immunity, Innate; Intercellular Adhesion Molecule-1; Interferon Type I; Membrane Proteins; Mice; Receptor, Interferon alpha-beta; Signal Transduction; T-Lymphocytes; Transendothelial and Transepithelial Migration; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1
PubMed: 34156982
DOI: 10.1172/jci.insight.149346 -
Medecine Sciences : M/S Dec 2011Phagocytes are the first line of host defense thanks to their capacity to infiltrate infected and wounded tissues, where they exert their bactericidal and tissue repair... (Review)
Review
Phagocytes are the first line of host defense thanks to their capacity to infiltrate infected and wounded tissues, where they exert their bactericidal and tissue repair functions. However, tissue infiltration of phagocytes also stimulates the progression of pathologies such as cancer and chronic inflammatory diseases. It is therefore necessary to identify the molecular and cellular mechanisms that control this process to identify new therapeutic targets. Phagocytes leave the blood stream by crossing the vascular wall and infiltrate interstitial tissues, a three-dimensional environment. A state-of-the-art of the different steps of phagocyte tissue recruitment in vivo and of the different in vitro models is developed in this synthesis. We focus on recent data concerning the migration of phagocytes in three-dimensional environments. The use of two different migration modes, amoeboid and mesenchymal, by macrophages and the role of podosomes and proteases in the mesenchymal migration are discussed.
Topics: Animals; Cell Movement; Cells, Cultured; Humans; Models, Biological; Neutrophil Infiltration; Phagocytes; Transendothelial and Transepithelial Migration
PubMed: 22192751
DOI: 10.1051/medsci/20112712018 -
Arteriosclerosis, Thrombosis, and... Sep 2014
Topics: Animals; Atherosclerosis; Carotid Artery Diseases; Chemotaxis, Leukocyte; Coronary Artery Disease; Humans; LIM Domain Proteins; Transcription Factors; Transendothelial and Transepithelial Migration
PubMed: 25142882
DOI: 10.1161/ATVBAHA.114.304151 -
Immunological Reviews Sep 2016
Topics: Animals; Cell Communication; Cell Degranulation; Cell Differentiation; Gene Expression Regulation; Humans; Immunity, Innate; Infections; Inflammation; Interleukin-8; Leukocyte Elastase; MicroRNAs; NADPH Oxidases; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 27558324
DOI: 10.1111/imr.12463 -
American Journal of Physiology. Lung... Aug 2021Electronic (e-) cigarettes are growing in popularity despite uncertainties regarding their long-term health implications. The link between cigarette smoking and... (Review)
Review
Electronic (e-) cigarettes are growing in popularity despite uncertainties regarding their long-term health implications. The link between cigarette smoking and initiation of chronic lung disease took decades to unpick so in vitro studies mimicking e-cigarette exposure aim to detect early indicators of harm. In response to e-cigarette exposure, alveolar macrophages adopt a proinflammatory phenotype of increased secretion of proinflammatory cytokines, reduction in phagocytosis, and efferocytosis and reactive oxygen species generation. These effects are largely driven by free radical exposure, changes in PI3K/Akt signaling pathways, nicotine-induced reduction in phagocytosis receptors, and impaired lipid homeostasis leading to a foam-like lipid-laden phenotype. Neutrophils exhibit disrupted chemotaxis and transmigration to chemokines, reduced phagocytosis and bacterial killing, and an increase in protease secretion without corresponding antiproteases in response to e-cigarette exposure. This is driven by an altered ability to respond and to polarize toward chemoattractants, an activation of the p38 MAPK signaling pathway and inability to assemble NADPH oxidase. E-cigarettes induce lung epithelial cells to display decreased ciliary beat frequency and ion channel conductance as well as changes in chemokine secretion and surface protein expression. Changes in gene expression, mitochondrial function, and signaling pathways have been demonstrated in lung epithelial cells to explain these changes. Many functional outputs of alveolar macrophages, neutrophils, and lung epithelial cells have not been fully explored in the context of e-cigarette exposure and the underlying driving mechanisms are poorly understood. This review discusses current evidence surrounding the effects of e-cigarettes on alveolar macrophages, neutrophils, and lung epithelial cells with particular focus on the cellular mechanisms of change.
Topics: Alveolar Epithelial Cells; Animals; Chemokines; Electronic Nicotine Delivery Systems; Humans; Inflammation; Macrophages, Alveolar; Neutrophils; Phagocytosis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Transendothelial and Transepithelial Migration; Vaping
PubMed: 34009037
DOI: 10.1152/ajplung.00081.2021 -
The Journal of Clinical Investigation May 2020Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4+ T cells but the underlying...
Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4+ T cells but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEVs). Lama5 depletion affected LN structure with increased HEVs, upregulated chemokines, and cell adhesion molecules, and led to greater numbers of Tregs in the T cell zone. Mouse and human T cell transendothelial migration and T cell entry into LNs were suppressed by Lama5 through the receptors α6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific CD4+ T cell entry into the CR through HEVs, suppressed T cell activation, and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4/Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. This study delineated a stromal Lama5-T cell receptor axis that can be targeted for immune tolerance modulation.
Topics: Animals; Dystroglycans; Humans; Integrin alpha6; Laminin; Lymph Nodes; Lymphatic Vessels; Mice; Mice, Inbred C57BL; Mice, Knockout; Stromal Cells; T-Lymphocytes; T-Lymphocytes, Regulatory; Transendothelial and Transepithelial Migration; Transplantation Tolerance
PubMed: 32017712
DOI: 10.1172/JCI135099 -
Annals of Biomedical Engineering Apr 2012Metabolic oligosaccharide engineering is an emerging technology wherein non-natural monosaccharide analogs are exogenously supplied to living cells and are... (Review)
Review
Metabolic oligosaccharide engineering is an emerging technology wherein non-natural monosaccharide analogs are exogenously supplied to living cells and are biosynthetically incorporated into cell surface glycans. A recently reported application of this methodology employs fluorinated analogs of ManNAc, GlcNAc, and GalNAc to modulate selectin-mediated adhesion associated with leukocyte extravasation and cancer cell metastasis. This monograph outlines possible mechanisms underlying the altered adhesion observed in analog-treated cells; these range from the most straightforward explanation (e.g., structural changes to the selectin ligands ablate interaction with their receptors) to the alternative mechanism where the analogs inhibit or otherwise perturb ligand production to more indirect mechanisms (e.g., changes to the biophysical properties of the selectin binding partner, the nanoenviroment of the binding partners, or the entire cell surface).
Topics: Animals; Cell Adhesion; Humans; Leukocytes; Metabolic Engineering; Oligosaccharides; Selectins; Transendothelial and Transepithelial Migration
PubMed: 22037949
DOI: 10.1007/s10439-011-0450-y -
Scientific Reports Jun 2021Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We...
Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.
Topics: Animals; Animals, Genetically Modified; Blood Flow Velocity; Embryo, Nonmammalian; Endothelium, Vascular; Gene Expression Regulation, Neoplastic; Gene Ontology; Hemorheology; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Intravital Microscopy; Microfluidics; Microscopy, Confocal; Neoplastic Cells, Circulating; Quinazolines; RNA, Neoplasm; Signal Transduction; Sunitinib; Transendothelial and Transepithelial Migration; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Zebrafish
PubMed: 34162963
DOI: 10.1038/s41598-021-92515-2 -
American Journal of Physiology. Heart... Nov 2017Increased counts and priming of peripheral polymorphonuclear leukocytes (PMNLs) are associated with future or ongoing atherosclerosis; however, the role of PMNLs in...
Increased counts and priming of peripheral polymorphonuclear leukocytes (PMNLs) are associated with future or ongoing atherosclerosis; however, the role of PMNLs in enhancing monocyte transendothelial migration is still unclear. Our aims were to examine endothelial and monocyte activation, transmigration, and posttransmigration activation induced ex vivo by in vivo primed PMNLs and the effect of antioxidants on the activation. A unique ex vivo coculture system of three cell types was developed in this study, enabling interactions among the following: primary human umbilical vein endothelial cells (HUVECs), monocytes (THP-1 cell line), and in vivo primed PMNLs from hemodialysis (HD) patients and healthy control (HC) subjects. The interactions among these cells were examined, and an intervention with superoxide dismutase and catalase was performed. Preexposed HUVECs to HD/HC PMNLs showed a significant monocyte transmigration yield, 120-170% above HCs. Monocyte exposure to HD PMNLs induced pre- and posttransmigration activation. When the three cell types were cocultivated at the same time, monocyte chemoattractant protein-1 protein levels released from HUVECs, and activation markers on HUVECs [CD54 and chemokine (C-X3-C motif) ligand 1] and monocytes [chemokine (C-X3-C) receptor 1 and chemokine (C-C motif) receptor 2] were increased. Monocyte transmigration yield decreased to 70% (compared with HC subjects) due to adherence and accumulation of monocytes to HUVECs. When superoxide dismutase and catalase were used, reduced HUVEC and monocyte activation markers brought the transmigration yields to control levels and abolished accumulation of monocytes, emphasizing the role of superoxide in this process. We conclude that peripheral primed PMNLs play a pivotal role in enhancing monocyte transendotelial migration, the hallmark of the atherosclerotic process. Primed PMNLs can be used as a mediator and a biomarker of atherosclerosis even before plaque formation. Primed polymorphonuclear leukocytes are key mediators in monocyte transendothelial migration, a new understanding of the initiation of endothelial dysfunction and monocyte activation, transmigration, and accumulation in the subendothelial layer.
Topics: Atherosclerosis; Catalase; Cell Adhesion; Chemokine CCL2; Coculture Techniques; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Kidney Failure, Chronic; Macrophage Activation; Monocytes; Neutrophils; Renal Dialysis; Superoxide Dismutase; Transendothelial and Transepithelial Migration
PubMed: 28778910
DOI: 10.1152/ajpheart.00122.2017 -
Autophagy Dec 2021A defining feature of an inflammatory reaction is infiltration of neutrophils into tissues, a response that requires breaching of endothelial cells (ECs) that line the...
A defining feature of an inflammatory reaction is infiltration of neutrophils into tissues, a response that requires breaching of endothelial cells (ECs) that line the lumenal aspect of blood vessels. Dysregulated neutrophil trafficking is a hallmark of pathology, but details of the molecular mechanisms that terminate neutrophil breaching of venular walls remain unclear. In this work, we have identified EC autophagy as a negative regulator of neutrophil diapedesis in acute physiological inflammation. Specifically, , inflamed venular ECs upregulate autophagy, a response that is selectively localized to EC contacts and temporally aligned with the peak of neutrophil trafficking. Genetic ablation of EC autophagy leads to excessive neutrophil tissue infiltration in multiple inflammatory models and supports enhanced neutrophil transendothelial migration (TEM), while pharmacological induction of autophagy inhibits neutrophil migration. Mechanistically, autophagy machinery regulates the architecture of EC contacts and controls the reorganization and degradation of adhesion molecules, constituting a physiological brake on leukocyte trafficking.
Topics: Autophagy; Cell Adhesion; Cell Movement; Endothelial Cells; Endothelium, Vascular; Humans; Inflammation; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 34720030
DOI: 10.1080/15548627.2021.1987675