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Annual Review of Pathology 2011Neither the innate nor adaptive immune system "responds" unless leukocytes cross blood vessels. This process occurs through diapedesis, in which the leukocyte moves in... (Review)
Review
Neither the innate nor adaptive immune system "responds" unless leukocytes cross blood vessels. This process occurs through diapedesis, in which the leukocyte moves in an ameboid fashion through tightly apposed endothelial borders and, in some cases, through the endothelial cell itself. This review focuses on the active role of the endothelial cell in diapedesis. Several mechanisms play a critical role in transendothelial migration, including signals derived from clustering of apically disposed intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, disruption or loosening of adherens junctions, and targeted recycling of platelet/endothelial cell adhesion molecule and other molecules from the recently described lateral border recycling compartment. Surprisingly, many of the same molecules and mechanisms that regulate paracellular migration also control transcellular migration. A hypothesis that integrates the various known mechanisms of transmigration is proposed.
Topics: Animals; Cell Movement; Endothelium, Vascular; Humans; Inflammation; Leukocytes; Transendothelial and Transepithelial Migration
PubMed: 21073340
DOI: 10.1146/annurev-pathol-011110-130224 -
Advanced Science (Weinheim,... Jun 2023Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the...
Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin-rich protrusions generate complex push-pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropism.
Topics: Transendothelial and Transepithelial Migration; Endothelial Cells; Endothelium; Actins; Mechanical Phenomena; Neoplasms
PubMed: 37051804
DOI: 10.1002/advs.202206554 -
Arteriosclerosis, Thrombosis, and... Apr 2012Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In the setting of... (Review)
Review
Adenosine is an endogenously released purine nucleoside that signals via 4 widely expressed G protein-coupled receptors: A(1), A(2A), A(2B), and A(3). In the setting of inflammation, the generation and release of adenosine is greatly enhanced. Neutrophils play an important role in host defense against invading pathogens and are the cellular hallmark of acute inflammation. Neutrophils both release adenosine and can respond to it via expression of all 4 adenosine receptor subtypes. At low concentrations, adenosine can act via the A(1) and A(3) adenosine receptor subtypes to promote neutrophil chemotaxis and phagocytosis. At higher concentrations, adenosine acts at the lower-affinity A(2A) and A(2B) receptors to inhibit neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release. Modulation of neutrophil function by adenosine is relevant in a broad array of disease models, including ischemia reperfusion injury, sepsis, and noninfectious acute lung injury. This review will summarize relevant research in order to provide a framework for understanding how adenosine directly regulates various elements of neutrophil function.
Topics: Adenosine; Animals; Cell Adhesion; Cell Degranulation; Chemotaxis, Leukocyte; Humans; Inflammation; Neutrophil Activation; Neutrophils; Phagocytosis; Receptors, Purinergic P1; Respiratory Burst; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 22423037
DOI: 10.1161/ATVBAHA.111.226845 -
Blood May 2016Neutrophils are polymorphonuclear leukocytes of the phagocytic system that act as first line of host defense against invading pathogens but are also important mediators... (Review)
Review
Neutrophils are polymorphonuclear leukocytes of the phagocytic system that act as first line of host defense against invading pathogens but are also important mediators of inflammation-induced injury. In contrast to other members of the innate immune system, neutrophils are classically considered a homogenous population of terminally differentiated cells with a well-defined and highly conserved function. Indeed, their short lifespan, the absent proliferative capacity, their limited ability to produce large amounts of cytokines, and the failure to recirculate from the tissue to the bloodstream have sustained this idea. However, increasing evidence over the last decade has demonstrated an unexpected phenotypic heterogeneity and functional versatility of the neutrophil population. Far beyond their antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. These emerging discoveries open a new door to understand the role of neutrophils during homeostatic but also pathogenic immune processes. Thus, this review details novel insights of neutrophil phenotypic and functional heterogeneity during homeostasis and disease.
Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Cell Movement; Cellular Senescence; Homeostasis; Humans; Immunity, Innate; Immunophenotyping; Infections; Inflammation; Lymphatic System; Mice; Neoplasms; Neutrophils; Transcriptome; Transendothelial and Transepithelial Migration
PubMed: 27002116
DOI: 10.1182/blood-2016-01-688887 -
Seminars in Immunopathology Mar 2014Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level,... (Review)
Review
Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level, the mucosal barrier is regulated by tight junctions (TJs) that seal the paracellular space between adjacent epithelial cells. Transmembrane proteins within TJs include junctional adhesion molecules (JAMs) that belong to the cortical thymocyte marker for Xenopus family of proteins. JAM family encompasses three classical members (JAM-A, JAM-B, and JAM-C) and related molecules including JAM4, JAM-like protein, Coxsackie and adenovirus receptor (CAR), CAR-like membrane protein and endothelial cell-selective adhesion molecule. JAMs have multiple functions that include regulation of endothelial and epithelial paracellular permeability, leukocyte recruitment during inflammation, angiogenesis, cell migration, and proliferation. In this review, we summarize the current knowledge regarding the roles of the JAM family members in the regulation of mucosal homeostasis and leukocyte trafficking with a particular emphasis on barrier function and its perturbation during pathological inflammation.
Topics: Animals; Cell Adhesion Molecules; Homeostasis; Humans; Inflammation; Leukocytes; Mucous Membrane; Transendothelial and Transepithelial Migration
PubMed: 24667924
DOI: 10.1007/s00281-014-0421-0 -
JCI Insight Mar 2023Polymorphonuclear neutrophils (PMNs) play a critical role in clearing invading microbes and promoting tissue repair following infection/injury. However, dysregulated PMN...
Polymorphonuclear neutrophils (PMNs) play a critical role in clearing invading microbes and promoting tissue repair following infection/injury. However, dysregulated PMN trafficking and associated tissue damage is pathognomonic of numerous inflammatory mucosal diseases. The final step in PMN influx into mucosal lined organs (including the lungs, kidneys, skin, and gut) involves transepithelial migration (TEpM). The β2-integrin CD11b/CD18 plays an important role in mediating PMN intestinal trafficking, with recent studies highlighting that terminal fucose and GlcNAc glycans on CD11b/CD18 can be targeted to reduce TEpM. However, the role of the most abundant terminal glycan, sialic acid (Sia), in regulating PMN epithelial influx and mucosal inflammatory function is not well understood. Here we demonstrate that inhibiting sialidase-mediated removal of α2-3-linked Sia from CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo. Sialylation was also found to regulate critical PMN inflammatory effector functions, including degranulation and superoxide release. Finally, we demonstrate that sialidase inhibition reduces bacterial peptide-mediated CD11b/CD18 activation in PMN and blocks downstream intracellular signaling mediated by spleen tyrosine kinase (Syk) and p38 MAPK. These findings suggest that sialylated glycans on CD11b/CD18 represent potentially novel targets for ameliorating PMN-mediated tissue destruction in inflammatory mucosal diseases.
Topics: Intestinal Mucosa; Neuraminidase; Neutrophils; Polysaccharides; Transendothelial and Transepithelial Migration; CD11b Antigen; CD18 Antigens
PubMed: 36719745
DOI: 10.1172/jci.insight.167151 -
Frontiers in Immunology 2018Cell migration is indispensable for various biological processes including angiogenesis, wound healing, and immunity. In general, there are two different migration modes... (Review)
Review
Cell migration is indispensable for various biological processes including angiogenesis, wound healing, and immunity. In general, there are two different migration modes described, the mesenchymal migration mode and the amoeboid migration mode. Neutrophils rapidly migrate toward the sites of injury, infection, and inflammation using the amoeboid migration mode which is characterized by cell polarization and a high migration velocity. During site-directed trafficking of neutrophils from the blood stream into the inflamed tissue, neutrophils must first withstand shear stress while migrating on the 2-dimensional endothelial surface. Subsequently, they have to cross different physical barriers during the extravasation process including the squeezing through the compact endothelial monolayer that comprises the blood vessel, the underlining basement membrane and then the 3-dimensional meshwork of extracellular matrix (ECM) proteins in the tissue. Therefore, neutrophils have to rapidly switch between distinct migration modes such as intraluminal crawling, transmigration, and interstitial migration to pass these different confinements and mechanical barriers. The nucleus is the largest and stiffest organelle in every cell and is therefore the key cellular element involved in cellular migration through variable confinements. This review highlights the importance of nuclear deformation during neutrophil crossing of such confinements, with a focus on transendothelial migration and interstitial migration. We discuss the key molecular components involved in the nuclear shape changes that underlie neutrophil motility and squeezing through cellular and ECM barriers. Understanding the precise molecular mechanisms that orchestrate these distinct neutrophil migration modes introduces an opportunity to develop new therapeutic concepts for controlling pathological neutrophil-driven inflammation.
Topics: Animals; Cell Nucleus; Cellular Microenvironment; Humans; Immunity, Innate; Inflammation; Mice; Neutrophils; Nuclear Envelope; Pseudopodia; Receptors, Cytoplasmic and Nuclear; Transendothelial and Transepithelial Migration; Lamin B Receptor
PubMed: 30505310
DOI: 10.3389/fimmu.2018.02680 -
The American Journal of Pathology Mar 2020Calcium is an essential second messenger in endothelial cells and plays a pivotal role in regulating a number of physiologic processes, including cell migration,... (Review)
Review
Calcium is an essential second messenger in endothelial cells and plays a pivotal role in regulating a number of physiologic processes, including cell migration, angiogenesis, barrier function, and inflammation. An increase in intracellular Ca concentration can trigger a number of diverse signaling pathways under both physiologic and pathologic conditions. In this review, we discuss how calcium signaling pathways in endothelial cells play an essential role in affecting barrier function and facilitating inflammation. Inflammatory mediators, such as thrombin and histamine, increase intracellular calcium levels. This calcium influx causes adherens junction disassembly and cytoskeletal rearrangements to facilitate endothelial cell retraction and increased permeability. During inflammation endothelial cell calcium entry and the calcium-related signaling events also help facilitate several leukocyte-endothelial cell interactions, such as leukocyte rolling, adhesion, and ultimately transendothelial migration.
Topics: Calcium Signaling; Cell Adhesion; Cell Communication; Cell Movement; Cytoskeleton; Endothelial Cells; Humans; Inflammation; Leukocyte Rolling; Thrombin; Transendothelial and Transepithelial Migration
PubMed: 31866349
DOI: 10.1016/j.ajpath.2019.11.004 -
Trends in Immunology Sep 2015During infection, a subset of effector T cells seeds the lymphoid and non-lymphoid tissues and gives rise to tissue-resident memory T cells (TRM). Recent findings have... (Review)
Review
During infection, a subset of effector T cells seeds the lymphoid and non-lymphoid tissues and gives rise to tissue-resident memory T cells (TRM). Recent findings have provided insight into the molecular and cellular mechanisms underlying tissue instruction of TRM cell homing, as well as the programs involved in their retention and maintenance. We review these findings here, highlighting both common features and distinctions between CD4 TRM and CD8 TRM cells. In this context we examine the role of memory lymphocyte clusters (MLCs), and propose that the MLCs serve as an immediate response center consisting of TRM cells on standby, capable of detecting incoming pathogens and mounting robust local immune responses to contain and limit the spread of infectious agents.
Topics: Animals; Cell Survival; Chemokines; Host-Pathogen Interactions; Humans; Immunologic Memory; Leukocyte Rolling; Lymphocyte Activation; Lymphoid Progenitor Cells; Organ Specificity; Signal Transduction; T-Lymphocyte Subsets; Transendothelial and Transepithelial Migration
PubMed: 26282885
DOI: 10.1016/j.it.2015.07.002 -
Immunological Reviews Sep 2016Transendothelial migration (TEM) of polymorphonuclear leukocytes (PMN) involves a carefully orchestrated dialog of adhesion and signaling events between leukocyte and... (Review)
Review
Transendothelial migration (TEM) of polymorphonuclear leukocytes (PMN) involves a carefully orchestrated dialog of adhesion and signaling events between leukocyte and endothelial cell. This article focuses on the contribution of endothelial cells to transmigration. The initiation of TEM itself generally requires interaction of PECAM on the leukocyte with PECAM at the endothelial cell border. This is responsible for the transient elevation of cytosolic-free calcium ions in endothelium that is required for TEM and for recruitment of membrane from the lateral border recycling compartment (LBRC). TEM requires LBRC to move to the site at which TEM will take place and for VE-cadherin to move away. Targeting of the LBRC to this site likely precedes movement of VE-cadherin and may play a role in clearing VE-cadherin from the site of TEM. The process of TEM can be dissected into steps mediated by distinct pairs of PMN/endothelial interacting molecules. CD99 regulates a step at or close to the end of TEM. CD99 signals through soluble adenylyl cyclase to activate PKA to trigger ongoing targeted recycling of the LBRC. Paracellular transmigration predominates (≥90% of events) in the cremaster muscle circulation, but transcellular migration may be more important at sites such as the blood-brain barrier. Both processes involve many of the same molecules and recruitment of the LBRC.
Topics: Abdominal Muscles; Animals; Blood-Brain Barrier; Calcium Signaling; Endothelial Cells; Humans; Neutrophils; Platelet Endothelial Cell Adhesion Molecule-1; Protein Transport; Transendothelial and Transepithelial Migration
PubMed: 27558328
DOI: 10.1111/imr.12443