scholarly journals Endothelial cell-derived CD95 ligand serves as a chemokine in induction of neutrophil slow rolling and adhesion

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Liang Gao ◽  
Gülce Sila Gülcüler ◽  
Lieke Golbach ◽  
Helena Block ◽  
Alexander Zarbock ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Flow Chamber ◽  
Integrin Activation ◽  
Cd95 Ligand ◽  
Slow Rolling

Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells. In myeloid cells, CD95 triggers activation of Syk-Btk/PLCγ2/Rap1 signaling that ultimately leads to integrin activation. Excitingly, CD95-deficient myeloid cells exhibit impaired bacterial clearance in an animal model of sepsis induced by cecal ligation and puncture (CLP). Our data identify the cellular and molecular mechanisms underlying the chemoattractant effect of endothelial cell-derived CD95L in induction of neutrophil recruitment and support the use of therapeutic inhibition of CD95’s activity in inflammatory diseases.

scholarly journals C/EBPα initiates primitive myelopoiesis in pluripotent embryonic cells

Blood ◽  
2009 ◽  
Vol 114 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Yaoyao Chen ◽  
Ricardo M. B. Costa ◽  
Nick R. Love ◽  
Ximena Soto ◽  
Martin Roth ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Embryonic Cells ◽  
Single Factor ◽  
Pluripotent Cells ◽  
Highly Active ◽  
Vertebrate Embryos ◽  
Necessary And Sufficient

Abstract The molecular mechanisms that underlie the development of primitive myeloid cells in vertebrate embryos are not well understood. Here we characterize the role of cebpa during primitive myeloid cell development in Xenopus. We show that cebpa is one of the first known hematopoietic genes expressed in the embryo. Loss- and gain-of-function studies show that it is both necessary and sufficient for the development of functional myeloid cells. In addition, we show that cebpa misexpression leads to the precocious induction of myeloid cell markers in pluripotent prospective ectodermal cells, without the cells transitioning through a general mesodermal state. Finally, we use live imaging to show that cebpa-expressing cells exhibit many attributes of terminally differentiated myeloid cells, such as highly active migratory behavior, the ability to quickly and efficiently migrate toward wounds and phagocytose bacteria, and the ability to enter the circulation. Thus, C/EPBα is the first known single factor capable of initiating an entire myelopoiesis pathway in pluripotent cells in the embryo.

Angiopoietin-2 promotes myeloid cell infiltration in a β2-integrin–dependent manner

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 5050-5059 ◽  
Author(s):  
Alexander Scholz ◽  
Victoria Lang ◽  
Reinhard Henschler ◽  
Marcus Czabanka ◽  
Peter Vajkoczy ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Delayed Type Hypersensitivity ◽  
Cell Infiltration ◽  
Dependent Manner ◽  
Specific Expression ◽  
Β2 Integrin ◽  
Angiopoietin 2

Abstract In human inflammatory diseases, we identified endothelial angiopoietin-2 (Ang-2) expression to be strongly associated with inflammations mediated by myeloid cells but not lymphocytes. To identify the underlying mechanism, we made use of a transgenic mouse model with inducible endothelial cell-specific expression of Ang-2. In this model, in the absence of inflammatory stimuli, long-term expression of Ang-2 led to a time-dependent accumulation of myeloid cells in numerous organs, suggesting that Ang-2 is sufficient to recruit myeloid cells. In models of acute inflammation, such as delayed-type hypersensitivity and peritonitis, Ang-2 transgenic animals showed an increased responsiveness. Intravital fluorescence video microscopy revealed augmented cell adhesion as an underlying event. Consequently, we demonstrated that Ang-2 is able to induce strong monocyte adhesion under shear in vitro, which could be blocked by antibodies to β2-integrin. Taken together, our results describe Ang-2 as a novel, endothelial-derived regulator of myeloid cell infiltration that modulates β2-integrin–mediated adhesion in a paracrine manner.

scholarly journals Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells

2020 ◽  
Vol 31 (9) ◽  
pp. 1996-2012 ◽  
Author(s):  
Simon Melderis ◽  
Julia Hagenstein ◽  
Matthias Tobias Warkotsch ◽  
Julien Dang ◽  
Georg Rudolf Herrnstadt ◽  
...  
Keyword(s):  
Egf Receptor ◽  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Antibody Treatment ◽  
Treatment Dose ◽  
Egfr Ligand ◽  
Significant Amelioration ◽  
M1 Phenotype

BackgroundRecent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown.MethodsThe nephrotoxic nephritis model of GN was studied in AREG−/− mice after bone marrow transplantation, and in mice with myeloid cell–specific EGFR deficiency. Therapeutic utility of AREG neutralization was assessed. Furthermore, AREG's effects on renal cells and monocytes/macrophages (M/M) were analyzed. Finally, we evaluated AREG expression in human renal biopsies.ResultsRenal AREG mRNA was strongly upregulated in murine GN. Renal resident cells were the most functionally relevant source of AREG. Importantly, the observation that knockout mice showed significant amelioration of disease indicates that AREG is pathogenic in GN. AREG enhanced myeloid cell responses via inducing chemokine and colony stimulating factor 2 (CSF2) expression in kidney resident cells. Furthermore, AREG directly skewed M/M to a proinflammatory M1 phenotype and protected them from apoptosis. Consequently, anti-AREG antibody treatment dose-dependently ameliorated GN. Notably, selective abrogation of EGFR signaling in myeloid cells was sufficient to protect against nephritis. Finally, strong upregulation of AREG expression was also detected in kidneys of patients with two forms of crescentic GN.ConclusionsAREG is a proinflammatory mediator of GN via (1) enhancing renal pathogenic myeloid cell infiltration and (2) direct effects on M/M polarization, proliferation, and cytokine secretion. The AREG/EGFR axis is a potential therapeutic target for acute GN.

Activation of Triggering Receptor Expressed on Myeloid Cells-1 Protects Monocyte from Apoptosis through Regulation of Myeloid Cell Leukemia-1

2013 ◽  
Vol 118 (5) ◽  
pp. 1140-1149 ◽  
Author(s):  
MeiTing Cai ◽  
QiXing Chen ◽  
Chi Chen ◽  
XiWang Liu ◽  
JinChao Hou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cell Leukemia ◽  
Proinflammatory Response ◽  
Extracellular Signal Regulated Kinase ◽  
Viral Oncogene ◽  
Extracellular Signal ◽  
Monocyte Apoptosis ◽  
Oncogene Homologue

Abstract Background: Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. Methods: Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. Results: Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. Conclusions: TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal–regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1–mediated hyperinflammatory response in monocytes.

Abstract 641: The Role of Interleukin-23 in the Development of Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Aliia Fatkhullina ◽  
Iuliia Peshkova ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Chronic Inflammatory Disease ◽  
Lymphoid Cells ◽  
Efficient Manner ◽  
Mediators Of Inflammation

Atherosclerosis is lipid-driven chronic inflammatory disease of the arterial wall mediated by innate and adaptive immune responses. Inflammation promotes the development atherosclerotic plaques. Cytokines are soluble mediators of inflammation and important players in the pathogenesis of atherosclerosis. IL-23, a cytokine of IL-6/IL-12 cytokines superfamily is produced by myeloid cells and regulates the production of IL-17 and IL-22 by T helper IL-17 producing (Th17) cells, innate lymphoid cells of type 3 (ILC3) and gamma delta T cells in various auto-inflammatory diseases. IL-23R expression was also detected on myeloid cells but its role in regulation of myeloid cell function is not well defined. The level of IL-23 was shown to be upregulated in cardiovascular pathologies. Therefore, we decided to address the role of IL-23 in atherosclerosis using Il23p19 and Il23(R) receptor deficient mice. Surprisingly, atherosclerosis prone, Ldlr -/- mice transplanted with Il23p19 -/- or Il23r -/- bone marrow and fed with Western diet (WD) for 14 weeks demonstrated acceleration of atherosclerosis progression, which was characterized by increased accumulation of various hematopoietic cells in the aortas. Analysis of cytokine production unexpectedly revealed no changes in IL-17A and IFN-gamma production among CD4 T cells in the aortas. This effect was specific to aortas, as IL-17A production in the intestine of Il23p19 -/- mice was reduced, similarly to previously published observations. On the other hand, macrophages from Il23p19 -/- mice were able to uptake oxLDL in more efficient manner compared to wt controls, suggesting the regulatory role of IL-23 in foam cells formation. We also found enhanced inflammatory gene expression in aortas of Il23p19 -/- -> Ldlr -/- and Il23r -/- -> Ldlr -/- mice compared to wt controls. Overall our data suggest IL-17 independent atheroprotective role of IL-23.

scholarly journals Applying New Science for Old Medicines: Targeting Leukocyte-Endothelial Adhesions by Antiinflammatory Herbal Drugs

2010 ◽  
Vol 5 (8) ◽  
pp. 1934578X1000500
Author(s):  
Solomon Habtemariam
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Herbal Medicines ◽  
Herbal Drugs ◽  
In Vitro Methods

During the last two decades, considerable progress has been made in understanding the molecular mechanisms of the various leukocytes and endothelial cell adhesion molecules (cell adhesion molecules - CAMs) involved in cell-cell and cell matrix interactions. This understanding has opened up a new avenue of novel chemotherapeutic targets and bioassay models for inflammatory diseases. Recently developed In Vitro bioassays on leukocyte/endothelial cell adhesions can now offer rapid and inexpensive assessment methods for herbal medicines with claimed antiinflammatory uses. Through the use of these robust in vitro methods, active principles of herbal drugs can also be isolated thereby providing the opportunity of standardizations based on a known chemical standard(s) and pharmacology. This review highlights relevant leukocyte/endothelial CAMs targets, available in vitro methods and our strategic approach for herbal standardizations.

Retinoic acid–induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27Kip1

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2199-2206 ◽  
Author(s):  
Anna Dimberg ◽  
Fuad Bahram ◽  
Inger Karlberg ◽  
Lars-Gunnar Larsson ◽  
Kenneth Nilsson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Cyclin E ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
G1 Arrest ◽  
Down Regulation ◽  
Cycle Arrest

Abstract All-trans retinoic acid (ATRA) is a potential therapeutic agent for the treatment of hematopoietic malignancies, because of its function as an inducer of terminal differentiation of leukemic blasts. Although the efficacy of ATRA as an anticancer drug has been demonstrated by the successful treatment of acute promyelocytic leukemia (APL), the molecular mechanisms of ATRA-induced cell cycle arrest of myeloid cells have not been fully investigated. In this study, we show that the onset of ATRA-induced G0/G1 arrest of human monoblastic U-937 cells is linked to a sharp down-regulation of c-Myc and cyclin E levels and an increase in p21WAF1/CIP1 expression. This is followed by an increase in p27Kip1 protein expression due to enhanced protein stability. The importance of an early decrease in Myc expression for these events was demonstrated by the failure of a U-937 subline with constitutive exogenous expression of v-Myc to cell cycle arrest and regulate cyclin E and p27Kip1 in response to ATRA. Preceding the initiation of G1 arrest, a transient rise in retinoblastoma protein (pRb), p107, and cyclin A levels was detected. Later, a rapid fall in the levels of cyclins A and B and a coordinate dephosphorylation of pRb at Ser780, Ser795, and Ser807/811 coincided with the accumulation of cells in G1. These results thus identify a decrease in c-Myc and cyclin E levels and a posttranscriptional up-regulation of p27Kip1 as important early changes, and position them in the complex chain of events regulating ATRA-induced cell cycle arrest of myeloid cells.

scholarly journals Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay

2005 ◽  
Vol 93 (3) ◽  
pp. 317-323 ◽  
Author(s):  
Serafim Kiriakidis ◽  
Oliver Högemeier ◽  
Susanne Starcke ◽  
Frank Dombrowski ◽  
Jens Claus Hahne ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Chorioallantoic Membrane ◽  
Endothelial Cell Proliferation ◽  
Inhibition Of Angiogenesis ◽  
Chicken Chorioallantoic Membrane ◽  
Chorioallantoic Membrane Assay

Anti-angiogenic strategies are emerging as an important tool for the treatment of cancer and inflammatory diseases. In the present investigation we isolated several isoflavones from a tempeh (fermented soyabean) extract. The isolated isoflavones were identified as 5,7,4′-trihydroxyisoflavone (genistein), 7,4′-dihydroxyisoflavone (daidzein), 6,7,4′-trihydroxyisoflavone (factor 2), 7,8,4′-trihydroxyisoflavone (7,8,4′-TriOH) and 5,7,3′,4′-tetrahydroxyisoflavone (orobol). The effects on angiogenesis of these isoflavones were evaluated in the chicken chorioallantoic membrane assay; their capacity to inhibit vascular endothelial growth factor-induced endothelial cell proliferation and expression of the Ets 1 transcription factor, known to be implicated in the regulation of new blood vessel formation, were also investigated. We found that all isoflavones inhibited angiogenesis, albeit with different potencies. Compared with negative controls, which slightly inhibited in vivo angiogenesis by 6·30 %, genistein reduced angiogensis by 75·09 %, followed by orobol (67·96 %), factor 2 (56·77 %), daidzein (48·98 %) and 7,8,4′-TriOH (24·42 %). These compounds also inhibited endothelial cell proliferation, with orobol causing the greatest inhibition at lower concentrations. The isoflavones also inhibited Ets 1 expression, providing some insight into the molecular mechanisms of their action. Furthermore, the chemical structure of the different isoflavones suggests a structure–activity relationship. Our present findings suggest that the new isoflavones might be added to the list of low molecular mass therapeutic agents for the inhibition of angiogenesis.

Abstract 341: Protective Role of Myeloid Cell-specific Erbb3 Signaling After Transverse Aortic Constriction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Haifeng Yin ◽  
Amanda J Lessard ◽  
Joanne T deKay ◽  
Yodit Herrmann ◽  
Michael P Robich ◽  
...  
Keyword(s):  
Heart Failure ◽  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Protective Role ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Cardiac Progenitors ◽  
Erbb3 Signaling

Introduction: Understanding molecular mechanisms underlying cardiac hypertrophy is crucial for protecting against cardiac remodeling, or slowing down its destined pathway to heart failure. Recent studies revealed that myeloid cells play an important role in the regulation of hypertrophic remodeling. Neuregulin-1 (NRG-1) has been shown to play an essential role in the regulation of tissue-protective and pro-survival processes in response to tissue injury in the cardiovascular system. We find that NRG-1 receptors, including ErbB2 and ErbB3, are expressed and functionally active in cardiac myeloid cells. We hypothesized that the NRG-1/ErbB3 signaling in myeloid cells plays a protective role in cardiac hypertrophic remodeling. To test this hypothesis, we examined the effect of Erbb3 gene ablation in mouse myeloid cells on cardiac hypertrophic remodeling induced by pressure overload. Methods and results: Myeloid-specific ErbB3-deficient mice (ErbB3 MyeKO ) were generated by crossing Erbb3 -floxed mice with LysM-Cre transgenic mice. Cardiac hypertrophic remodeling was established in mice by transverse aortic constriction (TAC). Five days after TAC, survival was dramatically reduced in male ErbB3 MyeKO mice (20% vs. 90%, p=0.021 , MyeKO vs. MyeWT). The post-mortem examination of lung weight to body weight ratio suggested that acute pulmonary edema was developed in ERBB3 MyeKO mice. In order to determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3 MyeKO males, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. A significant accumulation of myeloid cells was found in control but not in ErbB3 MyeKO males. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and cardiac progenitors) in control but not ErbB3 MyeKO males. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3 MyeKO males after TAC. Conclusion: Our data highlight the important role of myeloid cell-specific ErbB3 signaling in the accumulation of myeloid cells that contributes to the development of compensatory hypertrophy and the prevention of acute heart failure in male mice.

Inhibition of E-Selectin Inflammatory Function by the Glycomimetic GMI-1070

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 851-851
Author(s):  
Scott I Simon ◽  
Shannon Chase ◽  
Helen Thackray ◽  
John L. Magnani ◽  
Ted Wun
Keyword(s):  
Whole Blood ◽  
Immune Surveillance ◽  
Flow Chamber ◽  
Cell Disease ◽  
Integrin Activation ◽  
Employment Equity ◽  
Rolling Velocity ◽  
Equity Ownership ◽  
Slow Rolling ◽  
Dose Dependent

Abstract Abstract 851FN2 Introduction: E-selectin expression by endothelium plays dual roles in inflammation by supporting slow rolling and subsequently eliciting integrin activation and arrest of leukocytes. This process may be important for immune surveillance. In a previous mouse model of sickle cell disease, E-selectin mediated outside-in signaling results in upregulated leukocyte Mac-1 and increased red cell capture, exacerbating vaso-occlusion. This process was attenuated by infusion of GMI-1070, a novel synthetic small molecule pan-selectin antagonist. GMI-1070 is now in Phase II clinical trial to determine efficacy in treatment of vaso-occlusive crisis (VOC) of sickle cell disease (SCD). Here, we studied its dose dependent effects in SCD subjects not in VOC on neutrophil activation and its effects on E-selectin mediated β2 integrin activation and rolling and arrest in shear flow. Methods: Samples were obtained from 4 SCD subjects not in VOC enrolled in a Phase I study of the effects of GMI-1070, a pan-selectin antagonist that preferentially inhibits E-selectin. An intravenous (IV) loading dose of 20 mg/kg was followed 10 hours later by a dose of 10 mg/kg. Samples were drawn before the loading dose, then 4 and 8 hours after the initial infusion. Polymorphonuclear Neutrophil (PMN) activation was analyzed in whole blood and isolated cell assays. Monoclonal antibodies and fluorescent-activated cell sorting (FACS) were used to assay expression of CD11b/CD18 (Mac-1), CD62L (L-selectin), and the high affinity active conformation of CD18 (327C) as markers of neutrophil activation. E-selectin mediated activation of CD18 was achieved in isolated PMN by incubating with E-selectin-IgG and goat antibody F(ab')2 fragment to crosslink E-selectin-IgG PMN activation was assessed by surface expression of high affinity CD18 by the mAb 327C and FACS in the presence of various concentrations of GMI-1070. PMN rolling and arrest on an inflammatory substrate was quantified using a lab on a chip assay. Whole blood or isolated PMN were perfused through a microfluidic flow chamber at a shear stress of 2 dynes/cm2. The flow chamber had immobilized E-selectin and ICAM-1 to support PMN rolling and adhesion. Video recordings of PMN interacting with this substrate were taken to quantify the number of rolling versus arrested cells and to measure rolling velocity in the presence of GMI-1070. Results: An inverse relationship between the serum concentration of GMI-1070 and either activated CD18 or upregulated CD11b was observed. In the flow chamber assays, 6 of 7 samples showed GMI-1070 diminished PMN arrest that also correlated with diminished integrin activation. Incubation of PMN with GMI-1070 blocked CD18 activation in response to E-selectin-IgG cross-linking, with an IC50 of 0.5 mM. PMN rolling and arrest was measured following shearing of isolated PMN on E-selectin and ICAM-1 using a lab on a chip assay. The mean rolling velocity of 2 mm/sec was increased to 6 mm/sec at a GMI-1070 concentration of 20 mM, with an IC50 of 5.5 mM for the increase in rolling velocity. In contrast, an IC50 = 0.8 mM was required to antagonize the fraction converting from rolling to arrest under shear flow. Summary and Conclusions: There was a dose dependent inhibitory effect on PMN activation after IV administration of GMI-1070 as measured in ex vivo whole blood samples in a small cohort of SCD subjects at steady state. A systematic study of the activity of GMI-1070 on isolated PMN revealed two distinct patterns of inhibition. At low concentrations (IC50 = 0.5mM), GMI-1070 effectively blocked the capacity of E-selectin to activate CD18, in response to cross-linked ligands, and mediate arrest. Only at higher concentrations (IC50 = 5.5mM) did we observe a significant alteration in the capacity of GMI-1070 to increase the rolling velocity and frequency of capture on a substrate of E-selectin under fluid shear stress. This differential capacity to alter function reveals that slow rolling, which is mediated by recognition of a number of sialylated ligands on the surface of PMN can be distinguished from the processes associated with the transition to arrest. Thus, treatment with GMI-1070 at doses that efficiently block vascular occlusion may spare some PMN rolling and immune surveillance function. Disclosures: Simon: GlycoMimetics Inc.: Research Funding. Chase:GlycoMimetics Inc.: Research Funding. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership.

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