-
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 -
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 -
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 -
Indian Journal of Dermatology,... 2018
Review
Topics: Dermis; Diagnosis, Differential; Epidermis; Foreign-Body Reaction; Humans; Skin Diseases; Transendothelial and Transepithelial Migration
PubMed: 30073986
DOI: 10.4103/ijdvl.IJDVL_396_17 -
Proceedings of the National Academy of... Apr 2017Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration...
Vasodilator-stimulated phosphoprotein (VASP) and Ena-VASP-like (EVL) are cytoskeletal effector proteins implicated in regulating cell morphology, adhesion, and migration in various cell types. However, the role of these proteins in T-cell motility, adhesion, and in vivo trafficking remains poorly understood. This study identifies a specific role for EVL and VASP in T-cell diapedesis and trafficking. We demonstrate that EVL and VASP are selectively required for activated T-cell trafficking but are not required for normal T-cell development or for naïve T-cell trafficking to lymph nodes and spleen. Using a model of multiple sclerosis, we show an impairment in trafficking of EVL/VASP-deficient activated T cells to the inflamed central nervous system of mice with experimental autoimmune encephalomyelitis. Additionally, we found a defect in trafficking of EVL/VASP double-knockout (dKO) T cells to the inflamed skin and secondary lymphoid organs. Deletion of EVL and VASP resulted in the impairment in α4 integrin (CD49d) expression and function. Unexpectedly, EVL/VASP dKO T cells did not exhibit alterations in shear-resistant adhesion to, or in crawling on, primary endothelial cells under physiologic shear forces. Instead, deletion of EVL and VASP impaired T-cell diapedesis. Furthermore, T-cell diapedesis became equivalent between control and EVL/VASP dKO T cells upon α4 integrin blockade. Overall, EVL and VASP selectively mediate activated T-cell trafficking by promoting the diapedesis step of transendothelial migration in a α4 integrin-dependent manner.
Topics: Actins; Animals; CD4-Positive T-Lymphocytes; Cell Adhesion; Cell Adhesion Molecules; Chemotaxis; Inflammation; Integrin alpha4; Lymphocyte Activation; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Phosphoproteins; T-Lymphocytes; Transendothelial and Transepithelial Migration
PubMed: 28320969
DOI: 10.1073/pnas.1701886114 -
Journal of Leukocyte Biology May 2020Dysregulated leukocyte diapedesis is a major contributor to acute severe inflammatory states like sepsis and acute respiratory distress syndrome, which are common...
Dysregulated leukocyte diapedesis is a major contributor to acute severe inflammatory states like sepsis and acute respiratory distress syndrome, which are common conditions in critically ill subjects. Endocan is a circulating proteoglycan that binds to the leukocyte integrin LFA-1 and blocks its interaction with its endothelial ligand ICAM-1, subsequently leading to the inhibition of leukocyte recruitment. Recent data have highlighted the hypothetic role of p14, endocan's major catabolite found in the bloodstream of septic patients, as a potential antagonist of endocan, thus participating in the regulation of acute inflammation. We hereby characterize the role of p14 as a biologic competitor of endocan, through assessment of its molecular interactions with LFA-1, endocan, and ICAM-1, as well as its effects on human leukocyte trafficking. Using immunodetection assay, we report that p14 can bind to LFA-1, thus inhibiting the interaction between LFA-1 and endocan, which in turn leads to the restoration of the ICAM-1/LFA-1 interaction. In primary human T cells trafficking assays, we underline the absence of effect of p14 on ICAM-1-dependent adhesion and migration, as well as on transendothelial migration. However, in those models, p14 reverses the antimigratory effect of endocan. To conclude, our study supports the hypothesis of an antagonistic role of p14 versus endocan in its effect on the LFA-1/ICAM-1-dependent human leukocyte recruitment.
Topics: Cell Adhesion; Chemotaxis, Leukocyte; Humans; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Neoplasm Proteins; Proteoglycans; T-Lymphocytes; Transendothelial and Transepithelial Migration
PubMed: 32272492
DOI: 10.1002/JLB.3AB0320-612RR -
International Journal of Molecular... May 2022Endothelial dysfunction during diabetes has been previously reported to be at least in part attributed to increased oxidized low‑density lipoprotein (oxLDL) levels...
Endothelial dysfunction during diabetes has been previously reported to be at least in part attributed to increased oxidized low‑density lipoprotein (oxLDL) levels mediated by high glucose (HG) levels. Endothelial inflammation increases the adhesiveness of monocytes to the endothelium in addition to increasing vascular permeability, promoting diabetic atherogenesis. In a previous study, it was reported that oxLDL treatment induced nucleotide‑binding domain and leucine‑rich repeat containing family, pyrin domain‑containing 3 inflammasome activation in endothelial cells (ECs) under HG conditions, in a manner that could be effectively reversed by rosmarinic acid. However, it remains unclear whether oxLDL‑mediated inflammasome activation can regulate the interaction between monocytes and ECs. The effects of oxLDL‑mediated inflammasome activation on endothelial permeability under HG conditions, in addition to the effects of rosmarinic acid on these oxLDL‑mediated processes, also remain poorly understood. Therefore, the present study aimed to elucidate the mechanisms involved in oxLDL‑induced endothelial permeability and monocyte diapedesis under HG conditions, in addition to the potential effects of rosmarinic acid. ECs were treated with oxLDL under HG conditions in the presence or absence of ROS scavengers mitoTEMPO and NAC, p38 inhibitor SB203580, FOXO1 inhibitor AS1842856 or transfected with the TXNIP siRNA, before protein expression levels of intercellular adhesion molecule 1 (ICAM‑1), vascular cell adhesion molecule‑1 (VCAM‑1), phosphorylated vascular endothelial‑cadherin (VE‑cadhedrin), VE‑cadherin and zonula occludens‑1 (ZO‑1) were measured by western blotting. In addition, adhesion assay and Transwell assays were performed. oxLDL was found to significantly increase the expression of ICAM‑1 and VCAM‑1 in ECs under HG conditions whilst also enhancing the adhesion of monocytes to ECs. This was found to be dependent on the reactive oxygen species (ROS)/p38 MAPK/forkhead box O1 (FOXO1)/thioredoxin interacting protein (TXNIP) signaling pathway. In addition, oxLDL‑stimulated ECs under HG conditions exhibited increased phosphorylated VE‑cadherin protein levels and decreased ZO‑1 protein expression levels compared with those in untreated ECs, suggesting increased endothelial permeability. Furthermore, monocyte transmigration through the endothelial monolayer was significantly increased by oxLDL treatment under HG conditions. These oxLDL‑mediated effects under HG conditions were also demonstrated to be dependent on this ROS/p38 MAPK/FOXO1/TXNIP signaling pathway. Subsequently, rosmarinic acid treatment significantly reversed oxLDL‑induced overexpression of adhesion molecules and monocyte‑EC adhesion, oxLDL‑induced endothelial junction hyperpermeability and monocyte transmigration through the endothelial monolayer under HG conditions, in a dose‑dependent manner. These results suggest that rosmarinic acid can exert a protective effect against oxLDL‑mediated endothelial dysfunction under HG conditions by reducing the interaction between monocytes and ECs in addition to preventing monocyte diapedesis.
Topics: Cell Adhesion; Cinnamates; Depsides; Endothelial Cells; Glucose; Lipoproteins, LDL; Monocytes; Transendothelial and Transepithelial Migration; Rosmarinic Acid
PubMed: 35315501
DOI: 10.3892/ijmm.2022.5125 -
Current Opinion in Hematology May 2012Leukocyte extravasation is a multistep process that is regulated at various levels. This review will highlight recent findings that define new regulatory mechanisms and... (Review)
Review
PURPOSE OF REVIEW
Leukocyte extravasation is a multistep process that is regulated at various levels. This review will highlight recent findings that define new regulatory mechanisms and novel activities in the process of leukocyte docking to the endothelium and diapedesis of leukocytes through the endothelial barrier of the vessel wall.
RECENT FINDINGS
Within the past 2-3 years, novel regulatory mechanisms have been identified that control or balance leukocyte extravasation at different steps of the extravasation process. First evidence was established for differences in the roles of intracellular factors that bind to integrins and support their activation. A cytokine was found that counteracts the activation of leukocyte integrins. Not only leukocyte integrins but also their ligands on endothelial cells were shown to arrange in clusters while supporting leukocyte-endothelial interactions. Recent progress was made in determining in vivo the route of leukocyte diapedesis through the endothelium of the blood vessel wall. Finally, novel mechanisms were found that control the opening of the endothelial barrier during diapedesis and others that determine directionality of diapedesis.
SUMMARY
Recent progress in our understanding of leukocyte extravasation has unraveled novel steps and mechanisms that control this process in vivo. These findings provide new insights into the mechanisms that balance the entry of leukocytes into tissue.
Topics: Endothelium, Vascular; Humans; Leukocyte Rolling; Leukocytes; Transendothelial and Transepithelial Migration
PubMed: 22395664
DOI: 10.1097/MOH.0b013e3283523e78 -
Blood Oct 2013Kindlin-3 is an integrin-binding focal adhesion adaptor absent in patients with leukocyte and platelet adhesion deficiency syndrome and is critical for firm...
Kindlin-3 is an integrin-binding focal adhesion adaptor absent in patients with leukocyte and platelet adhesion deficiency syndrome and is critical for firm integrin-dependent leukocyte adhesion. The role of this adaptor in leukocyte diapedesis has never been investigated. In the present study, the functions of Kindlin-3 in this process were investigated in effector T lymphocytes trafficking to various lymphoid and nonlymphoid tissues. In vitro, Kindlin-3-deficient T cells displayed severely impaired lymphocyte function antigen-1-dependent lymphocyte adhesion but partially conserved very late antigen-4 adhesiveness. In vivo, the number of adoptively transferred Kindlin-3-deficient T effectors was dramatically elevated in the circulating pool compared with normal effectors, and the Kindlin-3 mutant effectors failed to enter inflamed skin lesions. The frequency of Kindlin-3-deficient T effectors arrested on vessel walls within inflamed skin-draining lymph nodes was also reduced. Strikingly, however, Kindlin-3-deficient effector T cells accumulated inside these vessels at significantly higher numbers than their wild-type lymphocyte counterparts and successfully extravasated into inflamed lymph nodes. Nevertheless, on entering these organs, the interstitial motility of these lymphocytes was impaired. This is the first in vivo demonstration that Kindlin-3-stabilized integrin adhesions, although essential for lymphocyte arrest on blood vessels and interstitial motility, are not obligatory for leukocyte diapedesis.
Topics: Adoptive Transfer; Animals; Cell Adhesion; Cell Movement; Cytoskeletal Proteins; Dermatitis; Humans; Integrin alpha4beta1; Lymphadenitis; Lymphocyte Function-Associated Antigen-1; Mice; Mice, Inbred C57BL; T-Lymphocytes; Transendothelial and Transepithelial Migration; Vasculitis
PubMed: 23980064
DOI: 10.1182/blood-2013-04-495036 -
Tissue Barriers Jan 2017Toxoplasma gondii is a ubiquitous parasite and a prevalent food-borne parasitic pathogen. Infection of the host occurs principally through oral consumption of... (Review)
Review
Toxoplasma gondii is a ubiquitous parasite and a prevalent food-borne parasitic pathogen. Infection of the host occurs principally through oral consumption of contaminated food and water with the gastrointestinal tract being the primary route for entry into the host. To promote infection, T. gondii has evolved highly specialized strategies for rapid traversal of the single cell thick intestinal epithelial barrier. Parasite transmigration via the paracellular pathway between adjacent cells enables parasite dissemination to secondary sites of infection where chronic infection of muscle and brain tissue is established. It has recently been proposed that parasite interactions with the integral tight junction (TJ) protein occludin influences parasite transmigration of the intestinal epithelium. We review here the emerging mechanisms of T. gondii transmigration of the small intestinal epithelium alongside the developing role played in modulating the wider TJ-associated proteome to rewire host cell regulatory systems for the benefit of the parasite.
Topics: Animals; Humans; Intestinal Mucosa; Occludin; Tight Junctions; Toxoplasma; Transendothelial and Transepithelial Migration
PubMed: 28452683
DOI: 10.1080/21688370.2016.1273865