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Immunity Nov 2014Leukocyte migration through activated venular walls is a fundamental immune response that is prerequisite to the entry of effector cells such as neutrophils, monocytes,... (Review)
Review
Leukocyte migration through activated venular walls is a fundamental immune response that is prerequisite to the entry of effector cells such as neutrophils, monocytes, and effector T cells to sites of infection, injury, and stress within the interstitium. Stimulation of leukocytes is instrumental in this process with enhanced temporally controlled leukocyte adhesiveness and shape-changes promoting leukocyte attachment to the inner wall of blood vessels under hydrodynamic forces. This initiates polarized motility of leukocytes within and through venular walls and transient barrier disruption facilitated sequentially by stimulated vascular cells, i.e., endothelial cells and their associated pericytes. Perivascular cells such as macrophages and mast cells that act as tissue inflammatory sentinels can also directly and indirectly regulate the exit of leukocytes from the vascular lumen. In this review, we discuss current knowledge and open questions regarding the mechanisms involved in the interactions of different effector leukocytes with peripheral vessels in extralymphoid organs.
Topics: Blood Vessels; Cell Adhesion; Endothelium, Vascular; Humans; Inflammation; Integrins; Leukocytes; Macrophages; Mast Cells; Neutrophils; T-Lymphocytes; Transendothelial and Transepithelial Migration
PubMed: 25517612
DOI: 10.1016/j.immuni.2014.10.008 -
Blood May 2019Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting... (Review)
Review
Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood-endothelial cell (EC) barrier and exerting effector cell functions. The neutrophil recruitment cascade to inflamed tissues involves elements of neutrophil rolling, firm adhesion, and crawling onto the EC surface before extravasating by breaching the EC barrier. The interaction between neutrophils and ECs occurs via various adhesive modules and is a critical event determining the mode of neutrophil transmigration, either at the EC junction (paracellular) or directly through the EC body (transcellular). Once thought to be a homogenous entity, new evidence clearly points to the plasticity of neutrophil functions. This review will focus on recent advances in our understanding of the mechanism of the neutrophil transmigration process. It will discuss how neutrophil-EC interactions and the subsequent mode of diapedesis, junctional or nonjunctional, can be context dependent and how this plasticity may be exploited clinically.
Topics: Animals; Cell Adhesion; Cell Communication; Endothelial Cells; Humans; Inflammation; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 30898863
DOI: 10.1182/blood-2018-12-844605 -
Blood Jul 2022The extravasation of leukocytes is a critical step during inflammation that requires the localized opening of the endothelial barrier. This process is initiated by the...
The extravasation of leukocytes is a critical step during inflammation that requires the localized opening of the endothelial barrier. This process is initiated by the close interaction of leukocytes with various adhesion molecules such as ICAM-1 on the surface of endothelial cells. Here we reveal that mechanical forces generated by leukocyte-induced clustering of ICAM-1 synergize with fluid shear stress exerted by the flowing blood to increase endothelial plasma membrane tension and to activate the mechanosensitive cation channel PIEZO1. This leads to increases in [Ca2+]i and activation of downstream signaling events including phosphorylation of tyrosine kinases sarcoma (SRC) and protein tyrosine kinase 2 (PYK2), as well as of myosin light chain, resulting in opening of the endothelial barrier. Mice with endothelium-specific Piezo1 deficiency show decreased leukocyte extravasation in different inflammation models. Thus, leukocytes and the hemodynamic microenvironment synergize to mechanically activate endothelial PIEZO1 and subsequent downstream signaling to initiate leukocyte diapedesis.
Topics: Animals; Endothelial Cells; Endothelium, Vascular; Inflammation; Intercellular Adhesion Molecule-1; Ion Channels; Leukocytes; Mice; Transendothelial and Transepithelial Migration
PubMed: 35443048
DOI: 10.1182/blood.2021014614 -
Immunity Nov 2010Neutrophils are produced in the bone marrow from stem cells that proliferate and differentiate to mature neutrophils fully equipped with an armory of granules. These... (Review)
Review
Neutrophils are produced in the bone marrow from stem cells that proliferate and differentiate to mature neutrophils fully equipped with an armory of granules. These contain proteins that enable the neutrophil to deliver lethal hits against microorganisms, but also to cause great tissue damage. Neutrophils circulate in the blood as dormant cells. At sites of infection, endothelial cells capture bypassing neutrophils and guide them through the endothelial cell lining whereby the neutrophils are activated and tuned for the subsequent interaction with microbes. Once in tissues, neutrophils kill microorganisms by microbicidal agents liberated from granules or generated by metabolic activation. As a final act, neutrophils can extrude stands of DNA with bactericidal proteins attached that act as extracellular traps for microorganisms.
Topics: Animals; Anti-Infective Agents; Bone Marrow; Cell Adhesion; Cell Adhesion Molecules; Exocytosis; Hematopoiesis; Hematopoietic Stem Cells; Humans; Infections; Mice; Neutrophils; Phagocytosis; Secretory Vesicles; Transendothelial and Transepithelial Migration
PubMed: 21094463
DOI: 10.1016/j.immuni.2010.11.011 -
Frontiers in Immunology 2019L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983,... (Review)
Review
L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983, L-selectin has been extensively characterized as a tethering/rolling receptor. There is now mounting evidence in the literature to suggest that L-selectin plays a role in regulating monocyte protrusion during transendothelial migration (TEM). The N-terminal calcium-dependent (C-type) lectin domain of L-selectin interacts with numerous glycans, including sialyl Lewis X (sLe) for tethering/rolling and proteoglycans for TEM. Although the signals downstream of L-selectin-dependent adhesion are poorly understood, they will invariably involve the short 17 amino acid cytoplasmic tail. In this review we will detail the expression of L-selectin in different immune cell subsets, and its influence on cell behavior. We will list some of the diverse glycans known to support L-selectin-dependent adhesion, within luminal and abluminal regions of the vessel wall. We will describe how each domain within L-selectin contributes to adhesion, migration and signal transduction. A significant focus on the L-selectin cytoplasmic tail and its proposed contribution to signaling via the ezrin-radixin-moesin (ERM) family of proteins will be outlined. Finally, we will discuss how ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.
Topics: Animals; Cell Adhesion; Cell Movement; Humans; L-Selectin; Leukocytes; Ligands; Protein Domains; Signal Transduction; Transcription Factors; Transendothelial and Transepithelial Migration
PubMed: 31139190
DOI: 10.3389/fimmu.2019.01068 -
Immunity Sep 2021The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs)...
The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation.
Topics: Animals; Autophagy; Chemotaxis, Leukocyte; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Junctions; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 34363750
DOI: 10.1016/j.immuni.2021.07.012 -
Immunity Dec 2018Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy...
Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources.
Topics: Animals; Abdominal Muscles; Chemokine CXCL1; Chemokine CXCL2; Duffy Blood-Group System; Endothelial Cells; Gene Expression Profiling; Gene Expression Regulation; Intercellular Junctions; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neutrophils; Receptors, Cell Surface; Transendothelial and Transepithelial Migration; Tumor Necrosis Factor-alpha
PubMed: 30446388
DOI: 10.1016/j.immuni.2018.09.018 -
Nature Communications Aug 2021Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells....
Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.
Topics: Animals; Biomarkers, Tumor; Cell Aggregation; Cell Cycle; Cell Transformation, Neoplastic; Humans; Intercellular Adhesion Molecule-1; Lung Neoplasms; Mice; Neoplastic Cells, Circulating; Protein Interaction Domains and Motifs; Signal Transduction; Transendothelial and Transepithelial Migration; Triple Negative Breast Neoplasms
PubMed: 34381029
DOI: 10.1038/s41467-021-25189-z -
Blood Nov 2017CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the...
CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with β2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177 neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177 and CD177 neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177 neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with β2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177-driven cell activation enhanced surface β2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a β2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration.
Topics: Adult; CD18 Antigens; Chemokines; Extracellular Signal-Regulated MAP Kinases; Female; GPI-Linked Proteins; Humans; Isoantigens; MAP Kinase Signaling System; Male; Neutrophils; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Cell Surface; Transendothelial and Transepithelial Migration; src-Family Kinases
PubMed: 28807980
DOI: 10.1182/blood-2017-03-768507 -
Blood Jul 2022
Topics: Humans; Inflammation; Ion Channels; Leukocytes; Transendothelial and Transepithelial Migration
PubMed: 35862093
DOI: 10.1182/blood.2022016596