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The European Physical Journal. E, Soft... Jul 2021As part of the immune response, leukocytes can directly transmigrate through the body of endothelial cells or through the gap between adjacent endothelial cells. These...
As part of the immune response, leukocytes can directly transmigrate through the body of endothelial cells or through the gap between adjacent endothelial cells. These are known, respectively, as the transcellular and paracellular route of diapedesis. What determines the usage of one route over the other is unclear. A recently proposed tenertaxis hypothesis claims that leukocytes choose the path with less mechanical resistance against leukocyte protrusions. We examined this hypothesis using numerical simulation of the mechanical resistance during paracellular and transcellular protrusions. By using parameters based on human lung endothelium, our results show that the required force to breach the endothelium through the transcellular route is greater than paracellular route, in agreement with experiments. Moreover, experiments have demonstrated that manipulation of the relative strength between the two routes can make the transcellular route preferable. Our simulations have demonstrated this reversal and thus tentatively confirmed the hypothesis of tenertaxis.
Topics: Cell Movement; Endothelial Cells; Humans; Leukocytes; Mechanical Tests; Transendothelial and Transepithelial Migration
PubMed: 34236552
DOI: 10.1140/epje/s10189-021-00096-9 -
Frontiers in Immunology 2018Immune responses are dependent on the recruitment of leukocytes to the site of inflammation. The classical leukocyte recruitment cascade, consisting of capture, rolling,... (Review)
Review
Immune responses are dependent on the recruitment of leukocytes to the site of inflammation. The classical leukocyte recruitment cascade, consisting of capture, rolling, arrest, adhesion, crawling, and transendothelial migration, is thoroughly studied but mostly in model systems, such as the cremasteric microcirculation. This cascade paradigm, which is widely accepted, might be applicable to many tissues, however recruitment mechanisms might substantially vary in different organs. Over the last decade, several studies shed light on organ-specific mechanisms of leukocyte recruitment. An improved awareness of this matter opens new therapeutic windows and allows targeting inflammation in a tissue-specific manner. The aim of this review is to summarize the current understanding of the leukocyte recruitment in general and how this varies in different organs. In particular we focus on neutrophils, as these are the first circulating leukocytes to reach the site of inflammation. Specifically, the recruitment mechanism in large arteries, as well as vessels in the lungs, liver, and kidney will be addressed.
Topics: Animals; Aorta; Cell Movement; Humans; Inflammation; Kidney; Leukocytes; Liver; Lung; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 30538702
DOI: 10.3389/fimmu.2018.02739 -
Journal of Immunology (Baltimore, Md. :... Sep 2023B cells, like T cells, can infiltrate sites of inflammation, but the processes and B cell subsets involved are poorly understood. Using human cells and in vitro assays,...
B cells, like T cells, can infiltrate sites of inflammation, but the processes and B cell subsets involved are poorly understood. Using human cells and in vitro assays, we find only a very small number of B cells will adhere to TNF-activated (but not to resting) human microvascular endothelial cells (ECs) under conditions of venular flow and do so by binding to ICAM-1 and VCAM-1. CXCL13 and, to a lesser extent, CXCL10 bound to the ECs can increase adhesion and induce transendothelial migration (TEM) of adherent naive and memory B cells in 10-15 min through a process involving cell spreading, translocation of the microtubule organizing center (MTOC) into a trailing uropod, and interacting with EC activated leukocyte cell adhesion molecule. Engagement of the BCR by EC-bound anti-κ L chain Ab also increases adhesion and TEM of κ+ but not λ+ B cells. BCR-induced TEM takes 30-60 min, requires Syk activation, is initiated by B cell rounding up and translocation of the microtubule organizing center to the region of the B cell adjacent to the EC, and also uses EC activated leukocyte cell adhesion molecule for TEM. BCR engagement reduces the number of B cells responding to chemokines and preferentially stimulates TEM of CD27+ B cells that coexpress IgD, with or without IgM, as well as CD43. RNA-sequencing analysis suggests that peripheral blood CD19+CD27+CD43+IgD+ cells have increased expression of genes that support BCR activation as well as innate immune properties in comparison with total peripheral blood CD19+ cells.
Topics: Humans; Transendothelial and Transepithelial Migration; Activated-Leukocyte Cell Adhesion Molecule; Endothelial Cells; Cell Movement; Endothelium, Vascular; Chemokines; Antigens, CD; Cells, Cultured
PubMed: 37530585
DOI: 10.4049/jimmunol.2200887 -
Journal of Cell Science Apr 2021The migration of activated T cells across the blood-brain barrier (BBB) is a critical step in central nervous system (CNS) immune surveillance and inflammation. Whereas...
The migration of activated T cells across the blood-brain barrier (BBB) is a critical step in central nervous system (CNS) immune surveillance and inflammation. Whereas T cell diapedesis across the intact BBB seems to occur preferentially through the BBB cellular junctions, impaired BBB integrity during neuroinflammation is accompanied by increased transcellular T cell diapedesis. The underlying mechanisms directing T cells to paracellular versus transcellular sites of diapedesis across the BBB remain to be explored. By combining in vitro live-cell imaging of T cell migration across primary mouse brain microvascular endothelial cells (pMBMECs) under physiological flow with serial block-face scanning electron microscopy (SBF-SEM), we have identified BBB tricellular junctions as novel sites for T cell diapedesis across the BBB. Downregulated expression of tricellular junctional proteins or protein-based targeting of their interactions in pMBMEC monolayers correlated with enhanced transcellular T cell diapedesis, and abluminal presence of chemokines increased T cell diapedesis through tricellular junctions. Our observations assign an entirely novel role to BBB tricellular junctions in regulating T cell entry into the CNS. This article has an associated First Person interview with the first author of the paper.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Endothelial Cells; Mice; T-Lymphocytes; Tight Junctions; Transendothelial and Transepithelial Migration
PubMed: 33912914
DOI: 10.1242/jcs.253880 -
Advanced Science (Weinheim,... Feb 2024Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged....
Astrocyte-Derived Extracellular Vesicular miR-143-3p Dampens Autophagic Degradation of Endothelial Adhesion Molecules and Promotes Neutrophil Transendothelial Migration after Acute Brain Injury.
Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged. Through the analysis of EVs packaged miRNAs in plasma samples from patients with intracerebral hemorrhage (ICH), it is discovered that the level of EVs packaged miR-143-3p (EVs-miR-143-3p) correlates closely with perihematomal edema and neurological outcomes. Further study reveals that, upon ICH, EVs-miR-143-3p is robustly secreted by astrocytes and can shuttle into brain microvascular endothelial cells (BMECs). Heightened levels of miR-143-3p in BMECs induce the up-regulated expression of cell adhesion molecules (CAMs) that bind to circulating neutrophils and facilitate their transendothelial cell migration (TEM) into brain. Mechanism-wise, miR-143-3p directly targets ATP6V1A, resulting in impaired lysosomal hydrolysis ability and reduced autophagic degradation of CAMs. Importantly, a VCAM-1-targeting EVs system to selectively deliver miR-143-3p inhibitor to pathological BMECs is created, which shows satisfactory therapeutic effects in both ICH and traumatic brain injury (TBI) mouse models. In conclusion, the study highlights the causal role of EVs-miR-143-3p in BMECs' dysfunction in acute brain injury and demonstrates a proof of concept that engineered EVs can be devised as a potentially applicable nucleotide drug delivery system for the treatment of CNS disorders.
Topics: Humans; Animals; Mice; Endothelial Cells; Transendothelial and Transepithelial Migration; Astrocytes; Neutrophils; Brain Injuries; Cell Movement; Extracellular Vesicles; MicroRNAs
PubMed: 38044319
DOI: 10.1002/advs.202305339 -
Cell Reports Jan 2022Understanding how cytotoxic T lymphocytes (CTLs) efficiently leave the circulation to target cancer cells or contribute to inflammation is of high medical interest....
Understanding how cytotoxic T lymphocytes (CTLs) efficiently leave the circulation to target cancer cells or contribute to inflammation is of high medical interest. Here, we demonstrate that human central memory CTLs cross the endothelium in a predominantly paracellular fashion, whereas effector and effector memory CTLs cross the endothelium preferably in a transcellular fashion. We find that effector CTLs show a round morphology upon adhesion and induce a synapse-like interaction with the endothelium where ICAM-1 is distributed at the periphery. Moreover, the interaction of ICAM-1:β2integrin and endothelial-derived CX3CL1:CX3CR1 enables transcellular migration. Mechanistically, we find that ICAM-1 clustering recruits the SNARE-family protein SNAP23, as well as syntaxin-3 and -4, for the local release of endothelial-derived chemokines like CXCL1/8/10. In line, silencing of endothelial SNAP23 drives CTLs across the endothelium in a paracellular fashion. In conclusion, our data suggest that CTLs trigger local chemokine release from the endothelium through ICAM-1-driven signals driving transcellular migration.
Topics: Chemokine CX3CL1; Endothelium, Vascular; Humans; Qb-SNARE Proteins; Qc-SNARE Proteins; T-Lymphocytes, Cytotoxic; Transendothelial and Transepithelial Migration
PubMed: 35045291
DOI: 10.1016/j.celrep.2021.110243 -
Annals of Biomedical Engineering Apr 2012Application of mechanical force to bonds between selectins and their ligands is a requirement for these adhesion receptors to optimally perform functions that include... (Review)
Review
Application of mechanical force to bonds between selectins and their ligands is a requirement for these adhesion receptors to optimally perform functions that include leukocyte tethering and activation of stable adhesion. Although all three selectins are reported to signal from the outside-in subsequent to ligand binding, E-selectin is unique in its capacity to bind multiple sialyl Lewis x presenting ligands and mediate slow rolling on the order of a micron per second. A diverse set of ligands are recognized by E-selectin in the mouse, including ESL-1, CD44 (HCELL), and PSGL-1 which are critical in transition from slow rolling to arrest and for efficient transendothelial migration. The molecular recognition process is different in humans as L-selectin is a major ligand, which along with glycolipids constitute more than half of the E-selectin receptors on human polymorphonuclear neutrophils (PMN). In addition, E-selectin is most efficient at raising the affinity and avidity of CD18 integrins that supports PMN deceleration and trafficking to sites of acute inflammation. The mechanism is only partially understood but known to involve a rise in cytosolic calcium and tyrosine phosphorylation that activates p38 MAP kinase and Syk kinase, both of which transduce signals from clustered E-selectin ligands. In this review we highlight the molecular recognition and mechanical requirements of this process to reveal how E-selectin confers selectivity and efficiency of signaling for extravasation at sites of inflammation and the mechanism of action of a new glycomimetic antagonist targeted to the lectin domain that has shown efficacy in blocking neutrophil activation and adhesion on inflamed endothelium.
Topics: Acute Disease; Animals; CD18 Antigens; Calcium; E-Selectin; Humans; Hyaluronan Receptors; Inflammation; Ligands; MAP Kinase Signaling System; Membrane Glycoproteins; Mice; Neutrophil Activation; Neutrophils; Phosphorylation; Transendothelial and Transepithelial Migration; p38 Mitogen-Activated Protein Kinases
PubMed: 22271244
DOI: 10.1007/s10439-011-0507-y -
European Journal of Immunology Feb 2012A major focus of researchers studying leukocyte recruitment has been to identify and understand how cell surface endothelial adhesion molecules, cell-to-cell junctional...
A major focus of researchers studying leukocyte recruitment has been to identify and understand how cell surface endothelial adhesion molecules, cell-to-cell junctional protein complexes, secreted chemokines and chemoattractants, and the vessel basement membrane structure organization coordinate the process of leukocyte recruitment. As research expands beyond the components initially identified as being necessary for leukocyte recruitment, attention has turned to the structures that regulate endothelial cell-to-matrix adhesion. In this issue of the European Journal of Immunology, Parsons et al. [Eur. J. Immunol. 2012. 42: 436-446] identify new players in the regulation of neutrophil diapedesis (transendothelial migration), namely the focal adhesion proteins, paxillin and focal adhesion kinase (FAK). While understudied, and indeed previously underappreciated, in leukocyte diapedesis, this Commentary discusses how the work by Parsons et al. implicates FAK and paxillin in the proximal (leukocyte rolling) and distal (diapedesis) steps of the multistep adhesion cascade of leukocyte recruitment.
Topics: Endothelium; Focal Adhesion Protein-Tyrosine Kinases; Humans; Neutrophils; Paxillin; Transendothelial and Transepithelial Migration
PubMed: 22266717
DOI: 10.1002/eji.201142342 -
American Journal of Physiology. Heart... May 2016Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to... (Review)
Review
Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.
Topics: Animals; Cell Communication; Endothelial Cells; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis; Neoplasms; Signal Transduction; Transendothelial and Transepithelial Migration; Tumor Microenvironment
PubMed: 26993222
DOI: 10.1152/ajpheart.00042.2016 -
Immunity Mar 2020Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in...
Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.
Topics: Adult; Aged; Animals; Arthritis, Rheumatoid; Child; Child, Preschool; Complement C3; Female; Humans; Integrins; Lymphocyte Function-Associated Antigen-1; Lymphocytes; Male; Mice, Inbred C57BL; Middle Aged; Monocytes; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 32187519
DOI: 10.1016/j.immuni.2020.02.006