Klaus Ley

..This Review focuses on new aspects of one of the central paradigms of inflammation and immunity--the leukocyte adhesion cascade...

..Furthermore, convincing biochemical data suggest that these structures are distinct from lipid rafts...

..In this review, we discuss these and other processes associated with monocytic cell dynamics in the vascular wall and their role in the initiation and progression of atherosclerosis...

..These results document a novel mechanism of adhesion receptor- and pulmonary chemokine-dependent regulation of the migration of activated CD8+ T cells into an important nonlymphoid peripheral site (i.e., the normal/noninflamed lung)...

..However, blocking both Mac-1 and ICAM-1 had no greater effect than either blockade alone. We conclude that endothelial ICAM-1 is the main ligand responsible for slow leukocyte rolling mediated by Mac-1, but not LFA-1...

..Thus, the multiple roles of PSGL-1 may explain why targeting this single adhesion molecule results in attenuation of chronic murine ileitis, a disease previously resistant to antiadhesion molecule strategies...

..Here, we tested the hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells, which in turn promote atherosclerosis...

..Adoptively transferred Rag1(-/-) or WT thymocytes correct neutrophil counts in neutropenic nude mice. We conclude that the development of IL-17A-producing T-lineage cells requires an intact thymic epithelium, but not V(D)J recombination...

..We conclude that IL-17A regulates blood neutrophil counts by inducing G-CSF production mainly in nonhemopoietic cells. IL-17A controls the expansion of IL-17A-producing Tn cell populations through IL-17R...

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..We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation...

..Each sling effectively lays out a cell-autonomous adhesive substrate in front of neutrophils rolling at high shear stress during inflammation...

..This identifies a second neutrophil-activation pathway that is as important as activation through G protein-coupled receptors (GPCRs)...

..To define the mechanism, bone marrow transplantation (BMT) after lethal irradiation was used to generate apoE-/- chimeric mice deficient in platelet, but not endothelial, P-selectin...

..The key findings were confirmed in a sepsis-induced model of ALI. These findings may translate into improved clinical treatments for ALI...

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..Atherosclerosis induces the recruitment of macrophages and dendritic cells that support antigen presentation...

..Antibody blockade of the p40 subunit of IL-23 reduces neutrophil numbers in wild-type mice. These findings identify a major homeostatic mechanism for the regulation of neutrophil production in vivo...

..The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis...

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..p21-Activated kinase (PAK) is an effector of small GTPases and has been implicated in cell migration...

..Decreased barrier function suggests that defects in the epithelium may represent the primary source of SAMP ileitis susceptibility...

..This review provides an overview of signaling in rolling and adherent neutrophils...

..Our data revealed what we believe to be a previously unrecognized role of endothelial and epithelial CXCR2 in LPS-induced PMN recruitment and lung injury...

..We conclude that ICAM-1 and LFA-1 play critical roles in the recruitment of neutrophils into the alveolar space in aerosolized LPS-induced lung inflammation, and LFA-1 serves as a ligand of ICAM-1 in the lung...

..We conclude that the gamma isoform of PI-3K must be functional in leukocytes to allow efficient adhesion from rolling in response to chemokine stimulation...

..Our findings suggest that β(7) integrins play an essential role in spontaneous chronic ileitis in vivo by promoting homing of disease-exacerbating B cells to MLNs and other intestinal tissues...

..Furthermore, although clinical trials to evaluate the efficacy of targeting the CCL25/CCR9 axis for the treatment of Crohn's disease are being conducted, preclinical data in animal models of IBD are lacking...

..S1P may play an important role in the prevention of vascular complications of type 1 diabetes...

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..These findings provide a potential new paradigm in macrophage-mediated vascular inflammation, atherosclerosis, and neointimal hyperplasia after arterial injury...

..12/15-LO is expressed in a variety of cells, including vascular cells, adipocytes, macrophages, and cardiomyocytes. The purpose of this study was to determine which cellular source of 12/15-LO is important for atherosclerosis...

..Our data reveal a novel regulatory axis whereby neutrophils reduce iNKT cell responses, which may be important in shaping the extent of inflammation...

..Thus, pathogenic CD4+ T cells not only use the physiologic alpha4beta7/MAdCAM-1 pathway, but alternatively engage alpha4beta1 and L-selectin to recirculate to the chronically inflamed small intestine...

..These findings were confirmed in A2a(flox/flox) x LysM-cre mice. ATL202 was only effective when A2a was present on BM-derived cells. A2a agonists may be effective at curbing inflammatory lung tissue damage...

..This Review is focused on the signaling events during the interaction of neutrophils with the endothelium...

..This review discusses the nature of these molecules and the mechanisms involved in the early steps of monocyte recruitment into atherosclerotic lesion sites within the vessel wall...

..We conclude that IL-17A mediated suppression of IL-17F production and secretion requires IL-17RA and is relevant to maintain the normal set point of blood neutrophil counts in vivo...

..Each rolling neutrophil formed three to four long tethers that extended up to 16 μm behind the rolling cell...

..Our study shows that mycophenolic acid suppresses neutrophil production by inhibiting IL-17 expression, suggesting that measurement of this interleukin might be useful in estimating the risk of neutropenia in clinical settings...

..These data show that E-selectin- and chemokine-mediated arrest mechanisms are overlapping in this model and identify CXCR2 as an important neutrophil arrest chemokine in vivo...

..We conclude that human neutrophil rolling on E- or P-selectin induces the extended alpha(L)beta(2) integrin conformation through signaling triggered by PSGL-1 engagement...

..These data show that neutrophil Galpha(i2) is necessary for chemokine-induced arrest, which is relevant for neutrophil recruitment to sites of acute inflammation...

..L-selectin binding to PSGL-1 initiates tethering events that enable L-selectin-independent leukocyte-endothelial interactions. These findings provide a molecular mechanism for the inflammatory defects seen in L-selectin-deficient mice...

..We conclude that the PAK-PIX-GIT1 complex is critical for Erk-dependent myosin phosphorylation and vascular permeability...

..Our findings suggest that LDL and oxLDL, but not mmLDL, induce a dendritic cell-like phenotype in macrophages, suggesting that these cells may be able to present antigens and support an immune response...

..These findings reveal that the initiation of protein O glycosylation by ppGalNAcT-1 provides a distinctive repertoire of advantageous functions that support vascular responses and humoral immunity...

..Our data indicate that the commonly held belief that FTY720 blocks lymphocyte egress from lymph nodes cannot fully explain the lymphocyte dynamics observed with prolonged treatment...

..These neutrophil effects may limit the usefulness of global NF-kappaB inhibitors for the treatment of inflammatory diseases...

..The unexpected synergism between E- and P-selectins explains why neutrophil recruitment is enhanced when both selectins are expressed...

..Our results suggest a prominent role of IL-23 in the regulation of granulopoiesis and the prevalence of IL-17A-producing Tn cells...

..CXCL4 is a platelet-derived chemokine that promotes macrophage differentiation from monocytes. Deletion of the PF4 gene that encodes CXCL4 reduces atherosclerotic lesions in ApoE(-/-) mice...

..We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4...

..These findings confirm LPS-induced migration of PMN into the lung. For the first time, distinct transmigration steps into the different lung compartments are characterized in vivo...

..CONCLUSION: The data show that neutrophil rolling on E-selectin leads to partial activation of LFA-1, enabling LFA-1-dependent rolling on ICAM-1. This mechanism is likely to amplify and accelerate neutrophil recruitment in inflammation...

..We conclude that a dysregulated immune response in E(-/-)P(-/-) mice causes disease development, but is not necessary for elevated neutrophil counts...

..Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice...

..To determine whether selectin-mediated leukocyte-rolling velocity in inflamed venules in vivo is determined by wall shear rate (WSR) or by wall shear stress (WSS)...

..One example is benign ethnic neutropenia, which is found in some African Americans. Reduced and elevated neutrophil counts, even within the normal range, are associated with excess all-cause mortality...

..In diabetes, it is related to microvascular complications. We discovered AR expression in foam cells by gene chip screening and hypothesized that it may be relevant in atherosclerosis...

..90% in wild-type, CD62P-/-, and CD18-/- single mutants. Our data show that removing both P-selectin and CD18 integrins from mice leads to severe neutrophil recruitment defects and spontaneous pathology...

..This role of activated platelets in atherosclerosis is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall...

..In addition, platelets secrete neutrophil and endothelial activators inducing production of inflammatory cytokines. Thus, platelets are important amplifiers of acute inflammation...

..Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism...

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..This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues...

..Thus, both LFA-1 and Mac-1 contribute to slowing down rolling leukocytes, although LFA-1 is more important than Mac-1 in efficiently inducing firm adhesion...

..This review provides a conceptual framework for neutrophil recruitment from the flowing blood...

..Neutrophils also generate reactive oxygen species that induce vascular leakage. This review focuses on the mechanisms of neutrophil-mediated leakage...

..Silencing the expression of Sp1 by siRNA significantly decreased sell promoter activity in EL4 cells. We conclude that sell transcription is regulated by Mzf1, Klf2, Sp1, Ets1, and Irf1...

..Thus, improvement beyond the current understanding requires in silico models that can predict both cellular and microvillus deformation and experiments that allow measurement of forces acting on individual microvilli and tethers...

..For screening and drug validation, the tracker shows promise as an automated data collection tool...

..We conclude that chemoattractant-induced PMN margination in the pulmonary circulation can occur by two separate mechanisms, one of which requires L-selectin...

..The automated tracking system allows one, for the first time, to reliably track rolling leukocytes in vivo, thus eliminating possible investigator bias and increasing throughput...

..2005). Their data demonstrate the importance of oxidative modification of (unknown) adhesion molecules in regulating inflammation and lymphocyte homing...

..The aims of this study were to develop an efficient, high temporal resolution model for direct simulation of leukocyte rolling and conduct a study of load-bearing bonds using the model...

..This chapter focuses on the application of these techniques to study leukocyte interactions with the vascular wall and molecular surfaces...

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..Different leukocyte subsets appear to use different modalities of integrin activation during rolling and arrest at distinct endothelial sites...

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..Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo...

..Remarkably, no arrest chemokine for neutrophils under inflammatory conditions has been found so far...

..In this review we shall summarize what is known about leukocyte recruitment into the aortic wall during atherosclerosis with a focus on mouse model systems...

..Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation...

..Further improvements in the efficiency, availability, specificity and pharmacokinetics of selectin inhibitors, and specialized application routes and schedules, hold promise for therapeutic indications...

..These results demonstrate a crucial role for LFA-1 in retention of activated CD8 T cells in normal mouse lungs and in the progression of lethal injury in HA-Tg mice...

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..The rapid activation of eNOS by the non-nuclear actions of GR, therefore, represents an important cardiovascular protective effect of acute high-dose corticosteroid therapy...

..Thus, Vav proteins play an essential role coupling beta2 to Rho GTPases and regulating multiple integrin-induced events important in leukocyte adhesion and phagocytosis...

..Our findings indicate a high degree of functional specificity among sialyltransferases and a substantial role for ST3Gal-IV in selectin ligand formation...

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..The knowledge gained will improve the understanding of the inflammatory process and provide significant information pertinent to the development of potential anti-inflammatory therapies for future clinical use in patients. ..

..Milestones for the following years are listed in the timeline. ..

..These studies are designed to (1) provide insight into the molecular mechanisms of monocyte and platelet recruitment to atherosclerotic lesions and (2) test their relevance in an established model of arterial injury in apoE-/- mice. ..

..Since ultrasound is the most economical of the modern imaging modalities, cost savings in health care can also be expected from the proposed research. ..

..The proposed work may enable the design of interventions into the chemokine network to stabilize atherosclerotic plaques by reducing their content of inflammatory cells. ..

..Studies such as this can provide a rational basis for the development of potential therapies targeting adhesion molecules. ..

..The proposed work may enable the design of interventions into the chemokine network to stabilize atherosclerotic plaques by reducing their content of inflammatory cells. ..