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Leukocyte Recruitment (leukocyte + recruitment)

Distribution by Scientific Domains

Medical Sciences	100%

Distribution within Medical Sciences

Immunology	35%
Allergy & Clinical Immunology	5%

Selected Abstracts

Role of Platelets in Hypercholesterolemia-Induced Leukocyte Recruitment and Arteriolar Dysfunction

MICROCIRCULATION, Issue 5 2006
KAREN Y. STOKES
ABSTRACT Objective: To define the contribution of platelets, specifically platelet-associated P-selectin, to the altered venular and arteriolar responses induced by hypercholesterolemia. Methods: Leukocyte and platelet recruitment in cremasteric venules, and endothelium-dependent relaxation (EDR) in arterioles were determined using intravital videomicroscopy. Wild-type (WT) mice were placed on a normal or high cholesterol diet. Hypercholesterolemic mice were treated with blocking antibodies against either P-selectin or PSGL-1, or were depleted of neutrophils (ANS) or platelets (APS). Bone marrow chimeras (P-selectin deficiency in platelets, but not in endothelial cells) were produced by transplanting bone marrow from P-selectin,/, into WT mice (P-sel,/,, WT). Results: Hypercholesterolemia (HC) elicited the recruitment of adherent platelets and leukocytes in venules and an impaired EDR in arterioles. The exaggerated cell adhesion responses were absent in hypercholesterolemic mice treated with ANS, anti-P-selectin or anti-PSGL-1 antibodies and in P-sel,/,, WT chimeras. The hypercholesterolemia-induced impairment of arteriolar EDR was significantly blunted in mice rendered either neutropenic or thrombocytopenic, and in P-sel,/,, WT chimeras. Conclusions: The findings indicate that platelet-associated P-selectin contributes to the recruitment of leukocytes and platelets in venules of hypercholesterolemic mice and that the P-selectin-mediated adhesive interactions also contribute to the impaired arteriolar function induced by hypercholesterolemia. [source]

Blockade of KATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009
M. Figura
Ischemia/reperfusion injury in renal transplantation leads to slow or initial nonfunction, and predisposes to acute and chronic rejection. In fact, severe ischemia reperfusion injury can significantly reduce graft survival, even with modern immunosuppressive agents. One of the mechanisms by which ischemia/reperfusion causes injury is activation of endothelial cells resulting in inflammation. Although several therapies can be used to prevent leukocyte recruitment to ischemic vessels (e.g. antiadhesion molecule antibodies), there have been no clinical treatments reported that can prevent initial immediate neutrophil recruitment upon reperfusion. Using intravital microscopy, we describe abrogation of immediate neutrophil recruitment to ischemic microvessels by the KATP antagonist glibenclamide (GlyburideÔ). Further, we show that glibenclamide can reduce leukocyte recruitment in vitro under physiologic flow conditions. ATP-regulated potassium channels (KATP) are important in the control of cell membrane polarization. Here we describe profound hyperpolarization of endothelial cells during hypoxia, and the reduction of this hyperpolarization using glibenclamide. These findings suggest that control of endothelial membrane potential during ischemia may be an important therapeutic tool in avoiding ischemia/reperfusion injury, and therefore, enhancing transplant long-term function. [source]

Leukocyte Recruitment and the Acute Inflammatory Response

BRAIN PATHOLOGY, Issue 1 2000
Paul Kubes
Leukocyte recruitment is a hallmark feature of the inflammatory response. This review summarizes the generally accepted paradigm of leukocyte recruitment based on studies using intravital microscopy to visualize the microcirculation. The role of selectins and ,4 -integrin in rolling as well as integrin-mediated adhesion is discussed. However, it is becoming increasingly clear that the recruitment cascade within organs differs and therefore the review also attempts to highlight what is and is not known regarding leukocyte recruitment into the brain microvasculature. In the second part of this review, we provide some discussion of mechanisms by which the inflammatory response may be terminated. Particular emphasis on nuclear factor Nf,B and how IL10, IL13 and secreted leukocyte protease inhibitor (SLPI) may impact upon the Nf,B-dependent inflammatory response is presented. [source]

Butyrate inhibits leukocyte adhesion to endothelial cells via modulation of VCAM-1

INFLAMMATORY BOWEL DISEASES, Issue 2 2004
Thomas Menzel MD
Abstract Background Leukocyte recruitment to areas of inflammation depends on Integrin-VCAM/ICAM interaction. Blocking the vascular cell adhesion molecule (VCAM-1) and the intracellular adhesion molecule (ICAM-1) may have therapeutic benefit for the inflammatory component of bowel disease. Notably, the induction of ICAM and VCAM is mediated by a nuclear factor kappaB (NF-,B)-dependent mechanism. We investigated whether the anti-inflammatory properties of butyrate are mediated via the modulation of VCAM and ICAM on human endothelial cells. Methods VCAM-1 and ICAM-1 expression on human endothelial cells upon tumor necrosis factor-, (TNF-,) stimulation was assessd by FACS analysis. A monocyte adhesion assay was performed to evaluate the relevance of a modulated CAM-expression. Electrophoretic mobility shift assays were applied to investigate NF-,B activation. Results The observed butyrate-associated inhibition of monocyte adhesion to endothelial cells is associated with an inhibition of NF-,B activation in human endothelial cells. In this context, the observed suppression of the TNF-, induced VCAM-1 expression is likely to play an essential role. Conclusions Butyrate inhibits VCAM-1 mediated leukocyte adhesion to human endothelial cells. This inhibition may contribute to the anti-inflammatory effects of butyrate in patients with distal ulcerative colitis. [source]

Leukocyte Recruitment and the Acute Inflammatory Response

The interferon-inducible gene IFI16 secretome of endothelial cells drives the early steps of the inflammatory response

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2010
Rossella Baggetta
Abstract The IFN-inducible human IFI16 gene is highly expressed in endothelial cells as well as epithelial and hematopoietic tissues. Previous gene array analysis of human umbilical vein endothelial cells overexpressing IFI16 has revealed an increased expression of genes involved in inflammation and apoptosis. In this study, protein array analysis of the IFI16 secretome showed an increased production of chemokines, cytokines and adhesion molecules responsible for leukocyte chemotaxis. Functional analysis of the promoter for CCL20, the chemokine responsible for leukocyte recruitment in the early steps of inflammation, by site-specific mutation demonstrated that NF-,B is the main mediator of CCL20 induction at the transcriptional level. Finally, both Langerhans DC and B-lymphocyte migration triggered by supernatants from IFI16-overexpressing endothelial cells was partially inhibited by Ab inactivating CCL4, CCL5 and CCL20 chemokines. Altogether, these results demonstrate that the IFI16 gene, through its secretome, regulates proinflammatory activity of endothelial cells, thus corroborating its role in the early steps of inflammation. [source]

The role of MAPK in governing lymphocyte adhesion to and migration across the microvasculature in inflammatory bowel disease

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2009
Franco Scaldaferri
Abstract Lymphocyte recruitment is a key pathogenic event in inflammatory bowel disease (IBD). Adhesion of T cells to human intestinal microvascular endothelial cells (HIMEC) is mediated by ICAM-1, VCAM-1 and fractalkine (FKN), but the signaling molecules that orchestrate this process have yet to be identified. Because MAPK play an important role in the response of many cell types to pro-inflammatory stimuli, we assessed the functional role of p38 MAPK, p42/44 MAPK and JNK in the regulation of lymphocyte adhesion to and chemotaxis across the microvasculature in IBD. We found that the MAPK were phosphorylated in the bowel microvasculature and human intestinal fibroblasts of patients with IBD but not of healthy individuals. Stimulation of HIMEC with TNF- , triggered phosphorylation of the MAPK, and up-regulation of VCAM-1, FKN and ICAM-1. Blockade of p38 decreased the expression of all MAPK by 50% (p<0.01), whereas inhibition of p42/44 decreased the expression of ICAM-1 and FKN by 50% (p<0.01). Treatment of human intestinal fibroblasts with TNF- , elicited production of IL-8 and MCP-1, which was reduced (p<0.05) by blockade of p38 and p42/44. Finally, blockade of p38 and p42/44 reduced lymphocyte adhesion to (p<0.05) and transmigration across (p<0.05) HIMEC monolayers. These findings suggest a critical role for MAPK in governing lymphocyte influx into the gut in IBD patients, and their blockade may offer a molecular target for blockade of leukocyte recruitment to the intestine. [source]

SLIC-1/sorting nexin,20: A novel sorting nexin that directs subcellular distribution of PSGL-1

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2008
Ulrich
Abstract P-Selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein expressed on the surface of leukocytes that serves as the major ligand for the selectin family of adhesion molecules and functions in leukocyte tethering and rolling on activated endothelium and platelets. Previous studies have implicated the highly conserved cytoplasmic domain of PSGL-1 in regulating outside-in signaling of integrin activation. However, molecules that physically and functionally interact with this domain are not completely defined. Using a yeast two-hybrid screen with the cytoplasmic domain of PSGL-1 as bait, a novel protein designated selectin ligand interactor cytoplasmic-1 (SLIC-1) was isolated. Computer-based homology search revealed that SLIC-1 was the human orthologue for the previously identified mouse sorting nexin,20. Direct interaction between SLIC-1 and PSGL-1 was specific as indicated by co-immunoprecipitation and motif mapping. Colocalization experiments demonstrated that SLIC-1 contains a Phox homology domain that binds phosphoinositides and targets the PSGL-1/SLIC-1 complex to endosomes. Deficiency in the murine homologue of SLIC-1 did not modulate PSGL-1-dependent signaling nor alter neutrophil adhesion through PSGL-1. We conclude that SLIC-1 serves as a sorting molecule that cycles PSGL-1 into endosomes with no impact on leukocyte recruitment. [source]

Fc, receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcR, adaptor

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007
Yutaka Kanamaru
Abstract Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcR, adaptor. They express FcR,-associated Fc,RI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of Fc,RI, in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end-stage renal disease, in which large amounts of circulating IgA-immune complexes (IC) may mediate receptor activation. To analyze the involvement of Fc,RI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human Fc,RIR209L that cannot associate with FcR,. Like Fc,RIwt -Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. Fc,RI activation in Fc,RIwt, but not in Fc,RIR209L, Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti-glomerular basement membrane Ab-induced GN models. Receptor triggering of syngenically transferred Fc,RIwt Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. Fc,RIwt cross-linking on macrophages activated MAP kinases and production of TNF-, and MCP-1. Moreover, IgA-IC from IgAN patients activated Fc,RI and induced TNF-, production. Thus, Fc,RI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage. [source]

CD4+CD25+ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2006
Sabine Ring Dr.
Abstract CD4+CD25+ regulatory T cells (Treg) exert suppressive functions on effector T cells in vitro and in vivo. However, the exact cellular events that mediate this inhibitory action remain largely unclear. To elucidate these events, we used intravital microscopy in a model of contact hypersensitivity (CHS) and visualized the leukocyte-endothelium interaction at the site of antigen challenge in awake C57BL/6 mice. Injection of Treg i.v. into sensitized mice at the time of local hapten challenge significantly inhibited rolling and adhesion of endogenous leukocytes to the endothelium. A similar inhibition of leukocyte recruitment could be recorded after injection of Treg-derived tissue culture supernatant. Thus, these data indicate that soluble factors may account for the suppressive effects. Accordingly we found that IL-10, but not TGF-,, was produced by Treg upon stimulation and that addition of anti-IL-10 antibodies abrogated the suppressive effects of Treg and tissue culture supernatant in CHS reactions. Moreover, CD4+CD25+ T cells isolated from IL-10,/, mice were not able to suppress the immune response induced by hapten treatment in C57BL/6 mice. In conclusion, our data suggest that cytokine-dependent rather than cell-cell contact-dependent mechanisms play a pivotal role in the suppression of CHS reactions by Treg in vivo. [source]

CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first ,-strand of chemokine

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2005
Silvia Sebastiani
Abstract In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first ,-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4+ T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines. [source]

Mice with neonatally induced inactivation of the vascular cell adhesion molecule-1 fail to control the parasite in Toxoplasma encephalitis

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2003
Martina Deckert
Abstract Under various inflammatory conditions, cell adhesion molecules are up-regulated in the central nervous system (CNS) and may contribute to the recruitment of leukocytes to the brain. In the present study, the functional role of vascular cell adhesion molecule (VCAM)-1 in Toxoplasma encephalitis (TE) was addressed using VCAMflox/flox MxCre mice. Neonatal inactivation of the VCAM-1 gene resulted in a lack of induction of VCAM-1 on cerebral blood vessel endothelial cells, whereas the constitutive expression of VCAM-1 on choroid plexus epithelial cells and the ependymawas unaffected; in these animals, resistance to T.,gondii was abolished, and VCAMflox/flox MxCre mice died of chronic TE caused by a failure to control parasites in the CNS. Although leukocyte recruitment to the CNS was unimpaired, the B cell response was significantly reduced as evidenced by reduced serum levels of anti- T.,gondii -specific IgM and IgG antibodies. Furthermore, the frequency and activation state of intracerebral T.,gondii -specific T cells were decreased, and microglial activation was markedly reduced. Taken together, these data demonstrate the crucial requirement of VCAM-1-mediated immune reactions for the control of an intracerebral infectious pathogen, whereas other cell adhesion molecules can efficiently compensate for VCAM-1-mediated homing across cerebral blood vessels. [source]

Synovial mast cells: role in acute and chronic arthritis

IMMUNOLOGICAL REVIEWS, Issue 1 2007
Peter A. Nigrovic
Summary:, Mast cells reside in the normal synovium and increase strikingly in number in rheumatoid arthritis and other joint diseases. Given the broad spectrum of activity of this lineage, it has for decades been considered probable that mast cells are involved in the pathophysiology of synovitis. Recent work in murine arthritis has substantiated this suspicion, showing that mast cells can contribute importantly to the initiation of inflammatory arthritis. However, the role of the greatly expanded population of synovial mast cells in established arthritis remains unknown. Here we review the current understanding of mast cell function in acute arthritis and consider the potentially important influence of this cell on key processes within the chronically inflamed synovium, including leukocyte recruitment and activation, fibroblast proliferation, angiogenesis, matrix remodeling, and injury to collagen and bone. We also consider recent evidence supporting an immunomodulatory or anti-inflammatory role for mast cells as well as pharmacologic approaches to the mast cell as a therapeutic target in inflammatory arthritis. [source]

Chemokine receptor-dependent alloresponses

IMMUNOLOGICAL REVIEWS, Issue 1 2003
Wayne W. Hancock
Summary:, Immunologists have typically viewed alloreactivity schematically as a function of antigen presentation, expansion of alloreactive T and B cells within regional lymphoid tissues, and cellular infiltration and destruction of an allograft. Actual details of the steps between immune activation and accumulation of effector cells within a graft typically have not received much attention. However, just how cells ,know' to move to and migrate within a graft or not is proving to be of increasing interest, as the chemokine-dependent mechanisms underlying leukocyte recruitment to a transplant are dissected. Experimentally, chemokine receptor targeting can prolong or induce permanent allograft survival, despite preservation of alloresponses within secondary lymphoid tissues, whereas current immunosuppressive protocols have only modest effects on chemokine production and leukocyte homing. Recent knowledge of the chemokine-dependent nature of allograft rejection, acceptance, and tolerance induction are presented as a basis for understanding the rationale for preclinical trials of chemokine receptor-targeted therapies currently underway in primate recipients of solid organ allografts. [source]

Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease

INFLAMMATORY BOWEL DISEASES, Issue 4 2008
Rebecca Carey MD
Abstract Background: While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation. Methods: Patients with pediatric-onset IBD were enrolled at diagnosis and during therapy. Serum cytokine analysis was performed using Bioplex. STAT3 phosphorylation (pSTAT3) in peripheral blood leukocytes (PBLs) was assessed by flow cytometry. Immunohistochemistry of colonic mucosa was used to localize pSTAT3 and STAT3 target genes. Microarray analysis was used to determine RNA expression profiles from colon biopsies. Results: Circulating IL-6 was upregulated in active IBD patients at diagnosis and during therapy. STAT3 activation was increased in PB granulocytes, IL-6-stimulated CD3+/CD4+ lymphocytes, and affected colon biopsies of IBD patients. The frequency of pSTAT3+ PB granulocytes and colon epithelial and lamina propria cells was highly correlated with the degree of mucosal inflammation. Microarray and Ingenuity Systems bioinformatics analysis identified IL-6:STAT3-dependent biological networks upregulated in IBD patients which control leukocyte recruitment, HLA expression, angiogenesis, and tissue remodeling. Conclusions: A proinflammatory IL6:STAT3 biologic network is upregulated in active pediatric IBD patients at diagnosis and during therapy. Specific targeting of this network may be effective in reducing mucosal inflammation. (Inflamm Bowel Dis 2007) [source]

Down-regulation of endothelial adhesion molecules and leukocyte adhesion by treatment with superoxide dismutase is beneficial in chronic immune experimental colitis

INFLAMMATORY BOWEL DISEASES, Issue 10 2005
Joaquim Seguí PhD
Abstract Modulation of adhesion molecule expression that govern trafficking of leukocytes into the inflamed intestine is envisioned as a new strategy for treatment of inflammatory bowel disease (IBD). This study was designed to determine the impact of reducing oxidative stress on adhesion molecules expression and leukocyte recruitment in experimental chronic colitis. For that purpose, colitic interleukin-10 knockout and wild-type mice were studied. Groups of animals were treated with Cu/Zn superoxide dismutase (SOD1) 13 mg/kg/d or vehicle for either 7 or 14 days. Expression of vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 were determined; leukocyte-endothelial cell interactions in colonic venules were studied with intravital microscopy; and changes in colon pathology and biomarkers of colitis severity were determined. Development of colitis was associated with a marked increase in endothelial vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 expression, which were significantly reduced by treatment with SOD1. The increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of SOD1. This treatment markedly reduced colonic lipid hydroperoxidation, myeoloperoxidase activity, and plasma levels of serum amyloid A protein and resulted in significant, although modest, reductions in histologic damage score. The therapeutic value of SOD1 when administered prophylactically was assessed in the dextran sulfate sodium model of colitis with similar positive results. These results indicate that SOD1 affords significant amelioration of colonic inflammatory changes in experimental colitis. Down-regulation of adhesion molecule expression, reduction of lipid hydroperoxidation, and recruitment of leukocytes into the inflamed intestine contribute to this beneficial effect. [source]

The metastatic T-cell hybridoma antigen/P-selectin glycoprotein ligand 1 is required for hematogenous metastasis of lymphomas

INTERNATIONAL JOURNAL OF CANCER, Issue 12 2007
Geert Raes
Abstract Using variants of the murine BW5147 lymphoma cell-line, we have previously identified 3 monoclonal antibodies (MAbs) that discriminate between metastatic and nonmetastatic BW5147-derived T-cell hybridomas and lymphomas, as well as BW5147-unrelated T-lymphomas. These MAbs were reported to recognize an identical membrane-associated sialoglycoprotein, termed "metastatic T-cell hybridoma antigen" (MTH-Ag). Here, we document that the expression pattern of the MTH-Ag on metastatic and nonmetastatic BW5147 variants correlates with that of the P-selectin glycoprotein ligand 1 (PSGL-1), a sialomucin involved in leukocyte recruitment to sites of inflammation. Moreover, the MAbs against the MTH-Ag recognize PSGL-1 when it is transfected in MTH-Ag-negative BW5147 variants, suggesting that the MTH-Ag is PSGL-1. Overexpression of MTH-Ag/PSGL-1 in MTH-Ag-negative BW5147 variants did not affect their in vivo malignancy. Yet, down-regulation of MTH-Ag/PSGL-1 expression on metastatic, MTH-Ag-positive BW5147 variants, using an RNA interference (RNAi) approach, resulted, in a dose-dependent manner, in a significant reduction of liver and spleen colonization and a delay in mortality of the recipient mice upon intravenous inoculation. Collectively, these results demonstrate that, although MTH-Ag/PSGL-1 overexpression alone may not be sufficient for successful dissemination and organ colonization, MTH-Ag/PSGL-1 plays a critical role in hematogenous metastasis of lymphoid cancer cells. © 2007 Wiley-Liss, Inc. [source]

Role of cell adhesion molecules in leukocyte recruitment in the liver and gut

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2003
A. Ala
Summary. This article reviews the evidence that adhesion molecules are critical in leukocyte recirculation and pathogenesis of diseases affecting the closely related tissues of the liver and gut, which offer novel opportunities for treatment. [source]

Critical roles for thrombin in acute and chronic inflammation

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009
D. CHEN
Summary., Thrombin can amplify inflammation induced by other stimuli, either through ischemia (consequent upon thrombosis), indirectly through generation of downstream mediators such as activated protein C, or directly via signals through protease activated receptors (PAR). This paper will summarize recent data from our laboratory indicating that thrombin is required to initiate CCR2-dependent leukocyte recruitment and that it is the principal determinant of the outcome after vascular injury, via PAR-1 activation of a distinct subset of smooth muscle cell progenitors. In both, tissue factor (TF) initiates thrombin generation and the thrombin acts locally, exemplifying that the initiation phase can generate autocrine or paracrine signalling molecules. Thrombin is an important constituent of innate immunity, able to amplify and modify responses to invading pathogens or tissue damage. With novel anti-thrombin therapeutics and agents to target PAR, a new understanding of the importance of thrombin may allow the development of innovative anti-inflammatory strategies. [source]

Endothelial L-selectin ligand expression in nasal polyps

ALLERGY, Issue 1 2010
F. A. Ebbens
Abstract Background:, L-selectins on leukocytes and their counter-receptors on endothelial cells have been shown to be involved in leukocyte recruitment in chronic rhinosinusitis without nasal polyps (NP). Objectives:, The purpose of this study was to evaluate the expression level of functionally active endothelial L-selectin ligands in NP obtained from patients with NP of different etiology [simple NP, antro-choanal polyps (ACP) and cystic fibrosis (CF) NP] and inferior turbinate specimens of healthy controls and to compare these levels to the presence of various leukocyte subsets. Methods:, Nasal polyp specimens and healthy nasal mucosa specimens were obtained from patients undergoing surgery and were immunohistochemically stained with monoclonal antibodies detecting CD34, sialyl Lewis x (sLex) of sulfated extended core 1 lactosamines and various leukocyte subsets. Results:, All NP are characterized by a decrease in the number of CD34+ vessels. The number of eosinophils and the percentage of vessels expressing endothelial sulfated sLex epitopes is upregulated in all groups of simple NP. Tissue eosinophilia is increased in those patients with increased disease severity (acetyl salicylic acid intolerance), but the percentage of endothelial sulfated sLex epitopes is not. Results on CF NP are similar to those observed for simple NP. Antro-choanal polyps, on the contrary, are characterized by low numbers of tissue eosinophils and relatively few vessels expressing endothelial sulfated sLex epitopes. Conclusions:, Our results suggest that functionally active L-selectin ligands might play a role in guiding leukocyte traffic into NP in patients with simple NP and CF NP but not ACP. [source]

Brain Endothelial Adhesion Molecule Expression in Experimental Colitis

MICROCIRCULATION, Issue 2 2001
MIQUEL SANS
ABSTRACT Objectives: 1) To determine if endothelial expression of adhesion molecules involved in leukocyte recruitment is increased in the brain and other organs in four different models of experimental colitis, and 2) to investigate whether leukocyte infiltration occurs in the brain of colitic animals. Methods: Endothelial vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was quantified, using the dual radiolabeled antibody technique in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis, in mice with dextran sulfate sodium (DSS)-induced colitis, in SCID mice reconstituted with CD45RBhigh T-cells, and in IL-10,/, mice. Leukocyte infiltration in the brain of TNBS-induced colitic rats was assessed by myeloperoxidase activity and immunohistochemical staining with anti-CD45 monoclonal antibody. Results: Marked upregulation of brain endothelial VCAM-1 (2- to 5.5-fold) was consistently found in colitic animals in the four models studied. Brain VCAM-1 strongly correlated with colon VCAM-1 and colon weight. By contrast, upregulation of brain ICAM-1 in colitic animals was only observed in the CD45RBhigh transfer (3-fold) and the TNBS-induced (1.5-fold models). Heart and muscle VCAM-1 and ICAM-1 were not upregulated in colitic animals in the majority of models studied. There was no leukocyte infiltration into the brain of TNBS-induced colitic rats. Conclusions: Our study demonstrates a marked and specific upregulation of endothelial VCAM-1 in the brain of colitic animals. This activation of cerebral endothelial cells was not associated with an infiltration of leukocytes into brain tissue. [source]

Experimental Models To Investigate Inflammatory Processes in Chronic Venous Insufficiency

MICROCIRCULATION, Issue S1 2000
RONALD J. KORTHUIS
ABSTRACT Chronic venous insufficiency (CVI) is characterized by leukocyte adhesion and infiltration, venous hypertension and dilatation, and valvular dysfunction. The fact that activated white cells can direct a powerful cytotoxic arsenal at parenchymal cells following their extravasation into the tissues led to the original proposal that leukocytes may play a causative role in the pathogenesis of venous disease. A large body of subsequent work indicates that white blood cells are indeed activated in CVI. However, identification of the factors responsible for initiating leukosequestration and activation in such disorders and determination of whether these activated cells then contribute to the progression of venous disease have been hampered by the lack of appropriate animal models that accurately mimic the human condition. Tantalizing evidence suggesting that cyclical periods of ischemia and reperfusion (I/R) may occur in diseased regions of the skin is beginning to accumulate. As is the case with CVI, leukocyte infiltration is a prominent feature in I/R and activated neutrophils play a causative role in the reperfusion component of tissue injury via the targeted release of reactive oxygen metabolites and hydrolytic enzymes. In light of these considerations, many investigators have suggested that examining the mechanisms of I/R injury in skin and skeletal muscle, where ischemia is produced by arterial occlusion, may provide a relevant model for studying the pathogenesis of CVI. Others have suggested that venous occlusion may represent a more appropriate model, as this approach also produces the venous hypertension that is characteristic of the disease. The purpose of this review is to summarize the evidence pointing to the involvement of I/R and venous hypertension as causative factors in CVI-induced leukocyte recruitment. In addition, we will describe the evidence in favor of the view that white blood cells contribute to the pathogenesis of CVI. Finally, we will describe several different experimental models that have been used to examine the role of I/R-induced microvascular dysfunction as it may pertain to the development of CVI, together with a discussion of the relative advantages and limitations of the various models. [source]

ORIGINAL ARTICLE: Cellular Interaction Regulates Interleukin-8 Secretion by Granulosa-Lutein Cells and Monocytes/Macrophages

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009
Anna Po
Problem, Peri-ovulatory migration of leukocytes towards the follicle plays an important role during corpus luteum formation. In this study, we examined the secretion of the neutrophil chemoattractant interleukin (IL)-8 by ovarian GL cells and the role of monocytes in IL-8 secretion. Method of study, Granulosa-lutein cells were isolated from the pre-ovulatory follicle. After depletion of contaminating leukocytes, GL cells were co-cultured with the myelo-monocytic cell line THP-1. Intracellular IL-8 accumulation, IL-8 secretion, and chemotactic activity of cell culture media were examined. Results, Intracellular IL-8 was predominantly localized in the endoplasmatic reticulum-Golgi both in GL cells and in THP-1 cells. In co-cultured cells, intracellular IL-8-specific immunofluorescence and IL-8 secretion were increased compared with either GL cells or THP-1 cells that were cultured alone. Conditioned cell culture media from GL cells and THP-1 cells induced directed cell migration by neutrophils. Conclusion, Human GL cells constitutively synthesize IL-8. An increased IL-8 secretion by co-cultured GL cells and THP-1 cells suggest that GL cells and monocytes mutually induce chemokine secretion. An initial interaction between GL cells and ovarian leukocytes may therefore contribute to an increased chemokine release and leukocyte recruitment to the forming corpus luteum. [source]

Stimulation of Uterine Cell Cytokine Production By Ovarian Hormones

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2000
J.A. DELOIA
PROBLEM: Although leukocytes do not possess significant numbers of ovarian steroid hormone receptors, their numbers in the endometrium vary consistently, relative to the menstrual cycle. The possibility that cell types within the endometrium express leukocyte-attracting genes in response to ovarian hormones was investigated. METHOD OF STUDY: Endometrial biopsies were collected 10 days post-leutinizing hormone surge; the cell types were separated and cultured individually for 5 days in the presence of increasing amounts of estrogen or progesterone. Following culture, RNA was collected from cells and reverse-transcription-polymerase chain reaction was used to determine relative levels of gene expression of monocyte chemotactic proteins (MCP)-1, -2, and -3, and interleukin (IL)-12p35 and p40. RESULTS: Although both endometrial stroma and glands were able to make MCP mRNA, steady-state levels of gene expression did not vary significantly relative to hormone treatment. The same was found for the p35 molecule of the IL-12 gene; however, differences were observed for the p40 subunit. CONCLUSIONS: Within the human endometrium, chemokines other than MCP and IL-12 are most likely responsible for cycle-related leukocyte recruitment. [source]

Effect of Antibodies on Endothelium

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009
X. Zhang
Patients developing posttransplant antibodies against HLA and non-HLA antigens expressed by the endothelium of the graft undergo more frequent episodes of rejection and have decreased long-term graft survival. Antibodies against the endothelium can alter/damage the cells of the graft through several mechanisms. Historically, antibodies were thought to elicit endothelial cell injury via complement-dependent mechanisms. New research has shown that antibodies can also contribute to the process of transplant rejection by stimulating proinflammatory and proproliferation signals. Antibody ligation leads to several functional alterations in EC including Weibel Palade body exocytosis, leukocyte recruitment, growth factor expression and cell proliferation. In contrast, under certain circumstances, antibodies may induce prosurvival signals and graft accommodation. The signaling events regulating accommodation vs. rejection appear to be influenced by the specificity and concentration of the anti-HLA antibody and the degree of molecular aggregation. Knowledge of the HLA and non-HLA antibody-mediated signaling pathways has the potential to identify new therapeutic targets to promote accommodation and prevent acute and chronic antibody-mediated rejection. [source]

Blockade of KATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia

Resident Macrophages are Involved in Intestinal Transplantation-Associated Inflammation and Motoric Dysfunction of the Graft Muscularis

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2007
N. Schaefer
Gut manipulation and ischemia/reperfusion evoke an inflammatory response within the intestinal muscularis that contributes to dysmotility. We hypothesize that resident macrophages play a key role in initiating the inflammatory cascade. Isogenic small bowel transplantation was performed in Lewis rats. The impact of recovery of organs on muscularis inflammation was investigated by comparing cold whole-body perfusion after versus prior to recovery. The role of macrophages was investigated by transplantation of macrophage-depleted gut. Leukocytes were counted using muscularis whole mounts. Mediator expression was determined by real-time RT-PCR. Contractility was assessed in a standard organ bath. Both organ recovery and ischemia/reperfusion induced leukocyte recruitment and a significant upregulation in IL-6, MCP-1, ICAM-1 and iNOS mRNAs. Although organ recovery in cold ischemia prevented early gene expression, peak expression was not changed by modification of the recovery technique. Compared to controls, transplanted animals showed a 65% decrease in smooth muscle contractility. In contrast, transplanted macrophage-depleted isografts exhibited significant less leukocyte infiltration and only a 19% decrease in contractile activity. In summary, intestinal manipulation during recovery of organs initiates a functionally relevant inflammatory response within the intestinal muscularis that is massively intensified by the ischemia reperfusion injury. Resident muscularis macrophages participate in initiating this inflammatory response. [source]

Differential Chemokine and Chemokine Receptor Gene Induction by Ischemia, Alloantigen, and Gene Transfer in Cardiac Grafts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2003
Dongmei Chen
Transplantation of allogeneic grafts presents several challenges to the innate and adaptive immune systems including chemokine leukocyte recruitment, activation, and effector function. We defined the chemokines and receptors induced by the transplant procedure/ischemia injury, alloantigen and gene transfer vector administration in murine cardiac grafts. E1, E3 deleted AdRSV,gal was transferred into grafts at the time of transplantation, grafts were harvested after 1,14 days, and a pathway-specific cDNA array was used to evaluate the levels of 67 chemokine and chemokine receptor genes. Transplantation resulted in ischemic injury and induction of a number of similar genes in both the syngeneic and allogeneic grafts, such as CXCL1 and CXCL5, which increased dramatically on day 1 and returned rapidly to baseline in the syngeneic grafts. Alloantigen stimulated the adaptive immune response and induced the presence of more inflammatory genes within the grafts, particularly at later time points. The adenovirus vector induced a broader panel of genes, among them potent inflammatory chemokines CXCL9 and CXCL10, that are induced earlier or more strongly compared with alloantigen stimulation alone. As alloantigen and adenovirus vectors both induce similar sets of genes, targeting these molecules may not only inhibit alloimmunity, but also enhance the utility of the gene transfer vector. [source]

Induction of CCR2-dependent macrophage accumulation by oxidized phospholipids in the air-pouch model of inflammation

ARTHRITIS & RHEUMATISM, Issue 5 2009
Alexandra Kadl
Objective Macrophages are key players in the pathogenesis of rheumatoid synovitis as well as in atherosclerosis. To determine whether atherogenic oxidized phospholipids potentially contribute to synovial inflammation and subsequent monocyte/macrophage recruitment, we examined the effects of oxidized 1- palmitoyl-2-arachidonoyl- sn -3-glycero-phosphorylcholine (OxPAPC) on chemokine expression and leukocyte recruitment in a facsimile synovium in vivo using the murine air-pouch model. Methods Air pouches were raised by 2 injections of sterile air, and inflammation was induced by injecting either lipopolysaccharide (LPS) or OxPAPC into the pouch lumen. Inflammation was assessed by analysis of inflammatory gene expression using reverse transcription,polymerase chain reaction or immunohistochemical analysis, and leukocytes were quantified in the lavage fluid and in the pouch wall after staining with Giemsa or after enzymatic digestion followed by fluorescence-activated cell sorter analysis. Results Application of OxPAPC resulted in selective recruitment of monocyte/macrophages into the air-pouch wall, but not in the lumen. In contrast, LPS induced both monocyte and neutrophil accumulation in the pouch lumen as well as in the wall. LPS, but not OxPAPC, induced the expression of adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. OxPAPC increased the expression of the CCR2 ligands monocyte chemotactic protein 1 (MCP-1), MCP-3, and MCP-5, as well as RANTES and growth-related oncogene , (GRO,), while it down-regulated the expression of CCR2 on macrophages. Moreover, oxidized phospholipid,induced macrophage accumulation was abrogated in CCR2,/, mice. Conclusion These data demonstrate that oxidized phospholipids trigger a type of inflammatory response that leads to selective macrophage accumulation in vivo, a process relevant for the pathogenesis of chronic inflammatory rheumatic diseases. [source]

Junctional adhesion molecule C mediates leukocyte adhesion to rheumatoid arthritis synovium

ARTHRITIS & RHEUMATISM, Issue 10 2008
Bradley J. Rabquer
Objective Leukocyte infiltration into the rheumatoid arthritis (RA) synovium is a multistep process in which leukocytes leave the bloodstream and invade the synovial tissue (ST). Leukocyte transendothelial migration and adhesion to RA ST requires adhesion molecules on the surface of endothelial cells and RA ST fibroblasts. This study was undertaken to investigate the role of junctional adhesion molecule C (JAM-C) in mediating leukocyte recruitment and retention in the RA joint. Methods Immunohistologic analysis was performed on RA, osteoarthritis (OA), and normal ST samples to quantify JAM-C expression. Fibroblast JAM-C expression was also analyzed using Western blotting, cell surface enzyme-linked immunosorbent assay, and immunofluorescence. To determine the role of JAM-C in leukocyte retention in the RA synovium, in vitro and in situ adhesion assays and RA ST fibroblast transmigration assays were performed. Results JAM-C was highly expressed by RA ST lining cells, and its expression was increased in OA ST and RA ST endothelial cells compared with normal ST endothelial cells. JAM-C was also expressed on the surface of OA ST and RA ST fibroblasts. Furthermore, we demonstrated that myeloid U937 cell adhesion to both OA ST and RA ST fibroblasts and to RA ST was dependent on JAM-C. U937 cell migration through an RA ST fibroblast monolayer was enhanced in the presence of neutralizing antibodies against JAM-C. Conclusion Our results highlight the novel role of JAM-C in recruiting and retaining leukocytes in the RA synovium and suggest that targeting JAM-C may be important in combating inflammatory diseases such as RA. [source]