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Cardiovascular Research Aug 2015Leucocyte transendothelial migration (TEM) involves a co-operative series of interactions between surface molecules on the leucocyte and cognate counter-ligands on the... (Review)
Review
Leucocyte transendothelial migration (TEM) involves a co-operative series of interactions between surface molecules on the leucocyte and cognate counter-ligands on the endothelial cell. These interactions set up a cascade of signalling events inside the endothelial cell that both allow for the junctions to loosen and for membrane to be recruited from the lateral border recycling compartment (LBRC). The LBRC is thought to provide an increased surface area and unligated receptors to the leucocyte to continue the process. The relative importance of the individual adhesion/signalling molecules that promote transmigration may vary depending on the type of leucocyte, the vascular bed, the inflammatory stimulus, and the stage of the inflammatory response. However, the molecular interactions between leucocyte and endothelial cell activate signalling pathways that disengage the adherens and tight junctions and recruit the LBRC to the site of transmigration. With the exception of disengaging the junctions, similar molecules and mechanisms promote transcellular migration as paracellular migration of leucocytes. This review will discuss the molecular interactions and signalling pathways that regulate transmigration, and the common themes that emerge from studying TEM of different leucocyte subsets under different inflammatory conditions. We will also raise some unanswered questions in need of future research.
Topics: Animals; Endothelial Cells; Humans; Leukocytes; Signal Transduction; Tight Junctions; Transendothelial and Transepithelial Migration
PubMed: 25987544
DOI: 10.1093/cvr/cvv145 -
American Journal of Physiology. Heart... Feb 2021The integrin family, an indispensable part of cell-cell and cell-matrix interactions, consists of a group of heterodimeric adhesion receptors formed by α- and... (Review)
Review
The integrin family, an indispensable part of cell-cell and cell-matrix interactions, consists of a group of heterodimeric adhesion receptors formed by α- and β-integrin subunits. Their wide expression and unique bidirectional signaling pathways allow them to play roles in a variety of biological activities including blood clot formation, cell attachment, and migration. Evidence suggests that integrins are essential regulators of the initiation of acute inflammation, especially two key aspects of this process i.e., vascular permeability and leukocyte recruitment. This mini-review discusses the importance of integrins at the onset of the acute inflammatory response and outlines research advances regarding the function of integrins and their modulators at different stages of this process. Insights into the fine-tuning of integrin signaling during acute inflammation may inspire the design of new drugs for inflammatory diseases.
Topics: Animals; CD18 Antigens; Capillary Permeability; Cell Adhesion; Cell Communication; Chemotaxis, Leukocyte; Endothelium, Vascular; Humans; Inflammation; Inflammation Mediators; Integrin beta1; Leukocyte Rolling; Leukocytes; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 33337960
DOI: 10.1152/ajpheart.00518.2020 -
Journal of Innate Immunity 2013The recruitment of immune cells is crucial for the development of inflammatory processes. The classical recruitment cascade of neutrophils into inflamed tissues is well... (Review)
Review
The recruitment of immune cells is crucial for the development of inflammatory processes. The classical recruitment cascade of neutrophils into inflamed tissues is well understood and consists of capturing, rolling, slow rolling, arrest, postadhesion strengthening, crawling, and transmigration. While this commonly agreed paradigm might be applicable to most peripheral tissues, recruitment mechanisms may substantially vary in different organs such as the lung, liver, and kidney. These organs are highly specialized tissues with unique cell populations and structural organization, which enables them to fulfill their individual functions. The published research over the last decade has shed some light on organ-specific mechanisms of neutrophil recruitment and helped to generate a deeper understanding of the specific recruitment mechanisms involved in this process. The aim of this review is to highlight current concepts of tissue-specific differences and similarities of neutrophil recruitment into the lung, liver, and kidney.
Topics: Animals; Cell Movement; Humans; Kidney; Leukocyte Rolling; Liver; Lung; Neutrophils; Organ Specificity; Transendothelial and Transepithelial Migration
PubMed: 23257511
DOI: 10.1159/000345943 -
Journal of Innate Immunity 2013Recruitment of neutrophils from the blood circulation to sites of infection or injury is a key innate immune response against invading pathogens and tissue injury.... (Review)
Review
Recruitment of neutrophils from the blood circulation to sites of infection or injury is a key innate immune response against invading pathogens and tissue injury. However, if inappropriately triggered, excessive and/or prolonged, this host defence response can also lead to severe pathological disorders. The migration of all leucocytes out of the vasculature is classically described by the leucocyte adhesion cascade that depicts a well-characterised sequence of cellular and molecular events within the vascular lumen. Recent findings have now illustrated that beyond the vascular lumen, the breaching of the venular wall can also involve an analogous cascade of adhesive events. For neutrophils this involves a tightly regulated and sequential series of responses within venular walls, initiating with adhesive steps that guide neutrophils through endothelial cells lining the venular wall, followed by responses that mediate and regulate their migration through the pericyte sheath and the venular basement membrane. The present review aims to provide a brief summary of novel additions to the classical adhesion cascade within the vascular lumen and then to discuss the emergence of a second adhesion cascade for neutrophils within venular walls, the latter illustrating the intricacies and complexities of neutrophil transmigration.
Topics: Animals; Basement Membrane; Cell Adhesion; Cell Movement; Humans; Immunity, Innate; Leukocyte Rolling; Neutrophils; Transendothelial and Transepithelial Migration; Venules
PubMed: 23466407
DOI: 10.1159/000346659 -
Trends in Immunology Oct 2011Neutrophils are the all-terrain vehicle of the innate immune system because of their ability to gain entry into tissues and organs, and thus, play an essential role in... (Review)
Review
Neutrophils are the all-terrain vehicle of the innate immune system because of their ability to gain entry into tissues and organs, and thus, play an essential role in host defense. Exactly how this marvel of nature works is still incompletely understood. In the past 2-3 years, new players and processes have been identified in the endothelial-leukocyte adhesion cascade. Novel signaling pathways have been discovered in both the endothelium and the neutrophils that regulate various steps in the recruitment process. This review focuses on these emerging pathways and the mechanisms that regulate neutrophil recruitment across endothelium.
Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Chemokines; Chemotaxis, Leukocyte; Endothelium, Vascular; Humans; Immunity, Innate; Inflammation; Mice; Neutrophil Infiltration; Neutrophils; Receptors, Chemokine; Signal Transduction; Transendothelial and Transepithelial Migration
PubMed: 21839681
DOI: 10.1016/j.it.2011.06.009 -
Transplantation Feb 2017We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic...
BACKGROUND
We have previously reported on a novel organ-specific immunomodifying therapy that provides protection from early allograft rejection in the absence of systemic immunosuppressive drugs. This novel therapy is a nanobarrier membrane called ImmunoCloak, consisting of a matrix of laminin, proteoglycans, fibronectin, and collagens. The membrane "immunocloaks" the luminal surfaces within the renal vasculature by covering the point of contact between donor vascular endothelial cells and the recipient's immune cells, without adversely affecting renal function. The resulting nonthrombogenic and nonimmunogenic apical surface significantly delays the onset of rejection fivefold over untreated controls. Currently, our focus is to elucidate the mechanisms of protection provided by placement of the membrane.
METHODS
The mechanisms underlying the protective effect of the ImmunoCloak treatment was evaluated using human peripheral blood mononuclear cells and by testing for antigen presentation by cytokine/chemokine analysis using the Luminex platform, T cell allogeneic responses were measured by flow cytometry, and diapedesis was assessed using transwell plates.
RESULTS
We now report that ImmunoCloak interrupts antigen presentation thereby preventing early T cell activation and interferes with diapedesis. There was significant inhibition in the synthesis of proinflammatory cytokines with a concordant blockade of T cell-mediated responses. The placement of the ImmunoCloak also significantly reduced leukocyte migration through the endothelial cell layer by 93%.
CONCLUSIONS
Eliminating the need for nephrotoxic immunosuppressive drugs during the early posttransplant period could help to ameliorate the severity of delayed graft function and could provide a path to using more ischemically damaged renal allografts.
Topics: Allografts; Antigen Presentation; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cell Proliferation; Cells, Cultured; Coculture Techniques; Collagen; Extracellular Matrix Proteins; Fibronectins; Graft Rejection; Human Umbilical Vein Endothelial Cells; Humans; Immunotherapy; Laminin; Lectins, C-Type; Lymphocyte Activation; Membranes, Artificial; Nanoparticles; Proteoglycans; T-Lymphocytes; Time Factors; Transendothelial and Transepithelial Migration
PubMed: 27764033
DOI: 10.1097/TP.0000000000001537 -
European Journal of Immunology Jan 2022The migration of CD4 effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can...
The migration of CD4 effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T-cell diapedesis by RNA sequencing (RNA-seq). We identified the atypical chemokine receptor 1 (Ackr1) as one of the main candidate genes upregulated in pMBMECs favoring transcellular T-cell diapedesis. We confirmed upregulation of ACKR1 protein in pMBMECs promoting transcellular T-cell diapedesis and in venular endothelial cells in the CNS during EAE. Lack of endothelial ACKR1 reduced transcellular T-cell diapedesis across pMBMECs under physiological flow in vitro. Combining our previous observation that endothelial ACKR1 contributes to EAE pathogenesis by shuttling chemokines across the BBB, the present data support that ACKR1 mediated chemokine shuttling enhances transcellular T-cell diapedesis across the BBB during autoimmune neuroinflammation.
Topics: Animals; Mice; Blood-Brain Barrier; CD4-Positive T-Lymphocytes; Duffy Blood-Group System; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Memory T Cells; Mice, Knockout; Multiple Sclerosis; Receptors, Cell Surface; Transendothelial and Transepithelial Migration
PubMed: 34524684
DOI: 10.1002/eji.202149238 -
Frontiers in Immunology 2021High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to... (Review)
Review
High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3T cell-enriched areas with fewer CD20B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies. Here, we discuss the current insight into TU-HEV formation, function, and regulation in tumors and elaborate on the functional implication, opportunities, and challenges of TU-HEV formation for cancer immunotherapy.
Topics: Animals; Endothelial Cells; Humans; Immunotherapy; L-Selectin; Lymphocytes; Neoplasms; Sialomucins; Signal Transduction; Tertiary Lymphoid Structures; Transendothelial and Transepithelial Migration; Tumor Microenvironment; Venules
PubMed: 34484246
DOI: 10.3389/fimmu.2021.736670 -
Journal of Innate Immunity 2013The leukocytes of the innate immune system, especially neutrophils and monocytes, exit the circulation early in the response to local inflammation and infection. This is... (Review)
Review
The leukocytes of the innate immune system, especially neutrophils and monocytes, exit the circulation early in the response to local inflammation and infection. This is necessary to control and prevent the spread of infections before an adaptive immune response can be raised. The endothelial cells and the intercellular junctions that connect them form a barrier that leukocytes need to pass in order to get to the site of inflammation. The junctions are tightly regulated which ensures that leukocytes only exit when and where they are needed. This regulation is disturbed in many chronic inflammatory diseases which are characterized by ongoing recruitment and interstitial accumulation of leukocytes. In this review, we summarize the molecular mechanisms that regulate endothelial cell-cell junctions and prevent or permit leukocyte transendothelial migration.
Topics: Animals; Autoimmune Diseases; Blood Vessels; Cell Movement; Endothelial Cells; Humans; Immunity, Innate; Inflammation; Intercellular Junctions; Leukocyte Rolling; Leukocytes; Transendothelial and Transepithelial Migration
PubMed: 23571667
DOI: 10.1159/000348828 -
Biomedicine & Pharmacotherapy =... Jul 2020Post-stroke neural damage is a serious health concern which does not yet have an effective treatment. We have shown previously that Shuxuening injection (SXNI), a Ginkgo...
Shuxuening injection facilitates neurofunctional recovery via down-regulation of G-CSF-mediated granulocyte adhesion and diapedesis pathway in a subacute stroke mouse model.
Post-stroke neural damage is a serious health concern which does not yet have an effective treatment. We have shown previously that Shuxuening injection (SXNI), a Ginkgo biloba extract-based natural medicine, protects brain after an acute ischemic stroke, but its efficacy for post-stroke recovery is not known. This study was to investigate whether SXNI can improve the prognosis of stroke at a subacute phase. Mice with cerebral ischemia-reperfusion injury (CIRI) were established by middle cerebral artery occlusion (MCAO), and drugs or saline were injected by the tail vein every 12 h after reperfusion. The therapeutic effect of SXNI was evaluated by survival rate, modified neurologic severity scores (mNSS), open-field test, locomotive gait patterns, cerebral infarction volume, brain edema and histopathological changes. Subsequently, a combined method of RNA-seq and Ingenuity® Pathway Analysis (IPA) was performed to identify key targets and pathways of SXNI facilitating the prognosis of stroke in mouse brain. The results of the transcriptome analysis were verified by real time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), western blot (WB) and immunohistochemistry (IHC). The experimental results showed that in the new subacute stroke model, SXNI markedly improves the survival rate, neurological and motor functions and histopathological changes, and significantly reduces cerebral infarction and edema volume. RNA-seq analysis of subacute stroke mice with or without SXNI (3 mL/kg) indicated 963 differentially expressed genes (DEGs) with a fold change ≥ 1.5 and a P-value ≤ 0.01. IPA analysis of DEGs showed that granulocyte adhesion and diapedesis ranked first in the pathway ranking, and the most critical gene regulated by SXNI was G-csf. Simultaneously, RT-PCR, ELISA, WB and IHC results demonstrated that SXNI not only obviously reduced the mRNA expression levels of key genes G-csf, Sele and Mac-1 in this pathway, but also significantly decreased the protein expression levels of G-CSF in serum and E-selectin and MAC-1 in brain tissues. In summary, our research suggested that SXNI can exert a remarkable neurofunctional therapeutic effect on stroke mice via down-regulating G-CSF to inhibit granulocyte adhesion and diapedesis. This study provides experimental evidence that SXNI may fulfill the need for stroke medicine targeting specifically at the recovery stage.
Topics: Animals; Brain Ischemia; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Granulocyte Colony-Stimulating Factor; Granulocytes; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury; Stroke; Transendothelial and Transepithelial Migration
PubMed: 32417690
DOI: 10.1016/j.biopha.2020.110213