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Blood Jul 2022
Topics: Humans; Inflammation; Ion Channels; Leukocytes; Transendothelial and Transepithelial Migration
PubMed: 35862093
DOI: 10.1182/blood.2022016596 -
Advances in Immunology 2016The neutrophil transmigration across the blood endothelial cell barrier represents the prerequisite step of innate inflammation. Neutrophil recruitment to inflamed... (Review)
Review
The neutrophil transmigration across the blood endothelial cell barrier represents the prerequisite step of innate inflammation. Neutrophil recruitment to inflamed tissues occurs in a well-defined stepwise manner, which includes elements of neutrophil rolling, firm adhesion, and crawling onto the endothelial cell surface before transmigrating across the endothelial barrier. This latter step known as diapedesis can occur at the endothelial cell junction (paracellular) or directly through the endothelial cell body (transcellular). The extravasation cascade is controlled by series of engagement of various adhesive modules, which result in activation of bidirectional signals to neutrophils and endothelial cells for adequate cellular response. This review will focus on recent advances in our understanding of mechanism of leukocyte crawling and diapedesis, with an emphasis on leukocyte-endothelial interactions and the signaling pathways they transduce to determine the mode of diapedesis, junctional or nonjunctional. I will also discuss emerging evidence highlighting key differences in the two modes of diapedesis and why it is clinically important to understand specificity in the regulation of diapedesis.
Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Endothelial Cells; Endothelium, Vascular; Humans; Inflammation; Leukocytes; Neutrophils; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 26791857
DOI: 10.1016/bs.ai.2015.09.001 -
Nature Communications Nov 2022Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood...
Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood vessel wall. Here, we show that perivascular mast cells (MC) are key regulators of neutrophil behaviour within the sub-endothelial space of inflamed venules. Using confocal intravital microscopy, we observe directed abluminal neutrophil motility along pericyte processes towards perivascular MCs, a response that created neutrophil extravasation hotspots. Conversely, MC-deficiency and pharmacological or genetic blockade of IL-17A leads to impaired neutrophil sub-endothelial migration and breaching of the pericyte layer. Mechanistically, identifying MCs as a significant cellular source of IL-17A, we establish that MC-derived IL-17A regulates the enrichment of key effector molecules ICAM-1 and CXCL1 in nearby pericytes. Collectively, we identify a novel MC-IL-17A-pericyte axis as modulator of the final steps of neutrophil diapedesis, with potential translational implications for inflammatory disorders driven by increased neutrophil diapedesis.
Topics: Transendothelial and Transepithelial Migration; Neutrophils; Pericytes; Interleukin-17; Mast Cells
PubMed: 36396641
DOI: 10.1038/s41467-022-34695-7 -
Nature Communications Apr 2022Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and...
Programmed death-1 (PD-1) and its ligand PD-L1 are checkpoint molecules which regulate immune responses. Little is known about their functions in T cell migration and there are contradictory data about their roles in regulatory T cell (Treg) function. Here we show activated Tregs and CD4 effector T cells (Teffs) use PD-1/PD-L1 and CD80/PD-L1, respectively, to regulate transendothelial migration across lymphatic endothelial cells (LECs). Antibody blockade of Treg PD-1, Teff CD80 (the alternative ligand for PD-L1), or LEC PD-L1 impairs Treg or Teff migration in vitro and in vivo. PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate zipper junctional VE-cadherin, and through NFκB-p65 to up-regulate VCAM-1 expression on LECs. CD80/PD-L1 signaling up-regulates VCAM-1 through ERK and NFκB-p65. PD-1 and CD80 blockade reduces tumor egress of PD-1 fragile Tregs and Teffs into draining lymph nodes, respectively, and promotes tumor regression. These data provide roles for PD-L1 in cell migration and immune regulation.
Topics: B7-1 Antigen; B7-H1 Antigen; Endothelial Cells; Ligands; Phosphatidylinositol 3-Kinases; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Transendothelial and Transepithelial Migration; Vascular Cell Adhesion Molecule-1
PubMed: 35449134
DOI: 10.1038/s41467-022-29930-0 -
Frontiers in Bioscience (Landmark... Jan 2018Pericytes build together with endothelial cells the microvascular vessel wall. They have been mainly implicated in angiogenesis and maintenance of the blood brain... (Review)
Review
Pericytes build together with endothelial cells the microvascular vessel wall. They have been mainly implicated in angiogenesis and maintenance of the blood brain barrier, but there is accumulating evidence for an immunological function of pericytes. Occupying a strategic position between the blood stream and the interstitial space, pericytes are able to sense environmental cues from both sides in an organ-specific manner and serve as gatekeepers for innate immune cells. In addition, pericytes are able to interact with leukocytes mediated by adhesion molecules as well as chemokines and are involved from the development of leukocytes in the bone marrow to their migration to injured or infected areas in target tissues. During disease processes pericytes regulate blood flow, vascular permeability, and leukocyte recruitment, but also contribute to maladaptive tissue responses, such as fibrosis making pericytes an attractive therapeutic target.
Topics: Animals; Cell Communication; Endothelium, Vascular; Humans; Leukocytes; Monitoring, Immunologic; Pericytes; Transendothelial and Transepithelial Migration
PubMed: 28930571
DOI: 10.2741/4615 -
Cardiovascular Research Aug 2015Monocytes fundamentally contribute to immune surveillance and the inflammatory response in immunoinflammatory diseases like atherosclerosis. Recruitment of these cells... (Review)
Review
Monocytes fundamentally contribute to immune surveillance and the inflammatory response in immunoinflammatory diseases like atherosclerosis. Recruitment of these cells to the site of injury requires their trafficking across the blood vessel wall. A series of events, including capture, rolling, slow rolling, arrest, adhesion strengthening, and lateral locomotion, precede monocyte transmigration. Recent investigations have revealed new aspects of this cascade. This article revisits some conventional paradigms and selectively highlights new findings, including novel insights into monocyte differentiation and recently identified functional mediators, signalling pathways, and new structural aspects of monocyte extravasation. The emerging roles of endothelial junctional molecules like vascular endothelial-cadherin and the junctional adhesion molecule family, adhesion molecules such as intercellular adhesion molecule-1, molecules localized to the lateral border recycling compartment like cluster of differentiation 99, platelet/endothelial cell adhesion molecule-1, and poliovirus receptor (CD155), as well as other cell surface molecules such as cluster of differentiation 146 and ephrins in transendothelial migration are discussed.
Topics: Animals; Antigens, CD; CD146 Antigen; Cadherins; Calcium Signaling; Cell Differentiation; Endothelium, Vascular; Ephrins; Homeostasis; Humans; Junctional Adhesion Molecules; Monocytes; Transendothelial and Transepithelial Migration
PubMed: 25990461
DOI: 10.1093/cvr/cvv147 -
Journal of Cell Science Apr 2021During inflammation, leukocytes circulating in the blood stream exit the vasculature in a process called leukocyte transendothelial migration (TEM). The current paradigm... (Review)
Review
During inflammation, leukocytes circulating in the blood stream exit the vasculature in a process called leukocyte transendothelial migration (TEM). The current paradigm of this process comprises several well-established steps, including rolling, adhesion, crawling, diapedesis and sub-endothelial crawling. Nowadays, the role of the endothelium in transmigration is increasingly appreciated. It has been established that leukocyte exit sites on the endothelium and in the pericyte layer are in fact not random but instead may be specifically recognized by migrating leukocytes. Here, we review the concept of transmigration hotspots, specific sites in the endothelial and pericyte layer where most transmigration events take place. Chemokine cues, adhesion molecules and membrane protrusions as well as physical factors, such as endothelial junction stability, substrate stiffness, the presence of pericytes and basement membrane composition, may all contribute to local hotspot formation to facilitate leukocytes exiting the vasculature. In this Review, we discuss the biological relevance of such hotspots and put forward multiple mechanisms and factors that determine a functional TEM hotspot.
Topics: Cell Adhesion Molecules; Endothelium, Vascular; Leukocytes; Neutrophils; Pericytes; Transendothelial and Transepithelial Migration
PubMed: 33795378
DOI: 10.1242/jcs.255653 -
Small GTPases Jan 2017Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens. It serves as a protective response that involves... (Review)
Review
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens. It serves as a protective response that involves leukocytes, blood vessels and molecular mediators with the purpose to eliminate the initial cause of cell injury and to initiate tissue repair. Inflammation is tightly regulated by the body and is associated with transient crossing of leukocytes through the blood vessel wall, a process called transendothelial migration (TEM) or diapedesis. TEM is a close collaboration between leukocytes on one hand and the endothelium on the other. Limiting vascular leakage during TEM but also when the leukocyte has crossed the endothelium is essential for maintaining vascular homeostasis. Although many details have been uncovered during the recent years, the molecular mechanisms from the vascular part that drive TEM still shows significant gaps in our understanding. This review will focus on the local signals that are induced in the endothelium that regulate leukocyte TEM and simultaneous preservation of endothelial barrier function.
Topics: Endothelium; Humans; Leukocytes; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 27715453
DOI: 10.1080/21541248.2016.1197872 -
Cardiovascular Research Aug 2015Recruitment of leucocytes such as neutrophils to the extravascular space is a critical step of the inflammation process and plays a major role in the development of... (Review)
Review
Recruitment of leucocytes such as neutrophils to the extravascular space is a critical step of the inflammation process and plays a major role in the development of various diseases including several cardiovascular diseases. Neutrophils themselves play a very active role in that process by sensing their environment and responding to the extracellular cues by adhesion and de-adhesion, cellular shape changes, chemotactic migration, and other effector functions of cell activation. Those responses are co-ordinated by a number of cell surface receptors and their complex intracellular signal transduction pathways. Here, we review neutrophil signal transduction processes critical for recruitment to the site of inflammation. The two key requirements for neutrophil recruitment are the establishment of appropriate chemoattractant gradients and the intrinsic ability of the cells to migrate along those gradients. We will first discuss signalling steps required for sensing extracellular chemoattractants such as chemokines and lipid mediators and the processes (e.g. PI3-kinase pathways) leading to the translation of extracellular chemoattractant gradients to polarized cellular responses. We will then discuss signal transduction by leucocyte adhesion receptors (e.g. tyrosine kinase pathways) which are critical for adhesion to, and migration through the vessel wall. Finally, additional neutrophil signalling pathways with an indirect effect on the neutrophil recruitment process, e.g. through modulation of the inflammatory environment, will be discussed. Mechanistic understanding of these pathways provide better understanding of the inflammation process and may point to novel therapeutic strategies for controlling excessive inflammation during infection or tissue damage.
Topics: Animals; Humans; Neutrophil Infiltration; Receptors, Formyl Peptide; Receptors, Leukocyte-Adhesion; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 25998986
DOI: 10.1093/cvr/cvv159 -
The Journal of Clinical Investigation May 2020The physical integrity of endothelial cells (ECs) lining the blood vessels regulates the inflammatory response. Both innate immunity and inflammatory disorders hinge on...
The physical integrity of endothelial cells (ECs) lining the blood vessels regulates the inflammatory response. Both innate immunity and inflammatory disorders hinge on the EC-neutrophil interaction. Neutrophil binding, rolling, and migrating along and between ECs is associated with vascular permeability. In this issue of the JCI, Owen-Woods et al. tracked neutrophils in vivo in venules of mouse striated muscle and revealed how endothelial permeability can affect neutrophil trafficking. Strikingly, many neutrophils that migrated between EC junctions were able to rejoin the blood circulation. Further, the chemokine and neutrophil chemoattractant, CXCL1, drove this reverse transendothelial migration (rTEM). This paradigm-shifting study provides a mechanism for distal organ damage as well as an explanation for sepsis-associated acute respiratory distress syndrome.
Topics: Animals; Cell Movement; Chemokines; Endothelial Cells; Mice; Neutrophils; Transendothelial and Transepithelial Migration
PubMed: 32202515
DOI: 10.1172/JCI136259