Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration

2010 ◽  
Vol 109 (3) ◽  
pp. 758-767 ◽  
Author(s):  
Kristin N. Kornerup ◽  
Gary P. Salmon ◽  
Simon C. Pitchford ◽  
Wai L. Liu ◽  
Clive P. Page
Keyword(s):  
Inflammatory Responses ◽  
Functional Expression ◽  
Neutrophil Activation ◽  
Neutrophil Recruitment ◽  
Current Therapy ◽  
Adequate Treatment ◽  
Relative Contribution ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli

Previous studies in our laboratory have shown that platelets are essential for the migration of eosinophils into the lungs of allergic mice, and that this is dependent on the functional expression of platelet P-selectin. We sought to investigate whether the same is true for nonallergic, acute inflammatory stimuli administered to distinct anatomic compartments. Neutrophil trafficking was induced in two models, namely zymosan-induced peritonitis and LPS-induced lung inflammation, and the platelet dependence of these responses investigated utilizing mice rendered thrombocytopenic. The relative contribution of selectins was also investigated. The results presented herein clearly show that platelet depletion (>90%) significantly inhibits neutrophil recruitment in both models. In addition, we show that P-selectin glycoprotein ligand-1, but not P-selectin, is essential for neutrophil recruitment in mice in vivo, thus suggesting the existence of different regulatory mechanisms for the recruitment of leukocyte subsets in response to allergic and nonallergic stimuli. Further studies in human blood demonstrate that low-dose prothrombotic and pro-inflammatory stimuli (CCL17 or CCL22) synergize to induce platelet and neutrophil activation, as well as the formation of platelet-neutrophil conjugates. We conclude that adhesion between platelets and neutrophils in vivo is an important event in acute inflammatory responses. Targeting this interaction may be a successful strategy for inflammatory conditions where current therapy fails to provide adequate treatment.

scholarly journals Neutrophil recruitment inhibitory factor: a possible candidate for a novel cytokine

1992 ◽  
Vol 1 (1) ◽  
pp. 49-54 ◽  
Author(s):  
W. M. S. C. Tamashiro ◽  
B. M. Tavares-Murta ◽  
F. Q. Cunha ◽  
M. C. Roque-Barreira ◽  
R. M. D. Nogueira ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Inflammatory Responses ◽  
Neutrophil Migration ◽  
Gel Filtration ◽  
Inhibitory Effect ◽  
Neutrophil Recruitment ◽  
Tnf Α ◽  
Inflammatory Stimuli

Inhibitory effect upon neutrophil migration to the inflammatory focus was previously detected in the cell-free incubation fluid of lipopolysaccharide (LPS)-stimulated macrophage monolayers. In the present study we showed that the neutrophil recruitment inhibitory activity from this supernatant was mainly detected in a fraction (P2) obtained by gel filtration chromatography on Sephacryl S-300. P2 fraction was able to inhibit ‘in vivo’ neutrophil emigration induced by different inflammatory stimuli, but it did not affect ‘in vitro’ neutrophil chemotaxis induced by FMLP. When injected intravenously, P2 inhibited oedema induced by carrageenin or immunological stimulus but not the oedema induced by dextran, thus affecting cell-dependent inflammatory responses. It was observed that P2 also induced neutrophil migration when injected locally in peritoneal cavities. This activity was significantly reduced by pretreatment of the animals with dexamethasone. Cytokines, such as IL-8 and TNF-α that are known to exhibit inhibitory effect upon neutrophil migration, were not detected in P2 fraction by highly sensitive assays. Overall the results suggest the existence of a novel cytokine exhibiting ‘in vivo’ neutrophil inhibitory activity, referred as NRIF.

scholarly journals Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

2019 ◽  
Vol 9 (1) ◽  
pp. 25 ◽  
Author(s):  
Alí Alejo ◽  
Carolina Sánchez ◽  
Sylvie Amu ◽  
Padraic G. Fallon ◽  
Antonio Alcamí
Keyword(s):  
Inflammatory Responses ◽  
Protein A ◽  
Disease Model ◽  
Tnf Inhibitor ◽  
Critical Determinant ◽  
Viral Spread ◽  
Inflammatory Conditions ◽  
Decoy Receptors ◽  
Bifunctional Inhibitor

The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein. A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.

scholarly journals Biologic Complexity in Sickle Cell Disease: Implications for Developing Targeted Therapeutics

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Beatrice E. Gee
Keyword(s):  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Occlusion ◽  
Current Therapy ◽  
Cell Disease ◽  
Primary Defect ◽  
Relative Contribution ◽  
Hb S

Current therapy for sickle cell disease (SCD) is limited to supportive treatment of complications, red blood cell transfusions, hydroxyurea, and stem cell transplantation. Difficulty in the translation of mechanistically based therapies may be the result of a reductionist approach focused on individual pathways, without having demonstrated their relative contribution to SCD complications. Many pathophysiologic processes in SCD are likely to interact simultaneously to contribute to acute vaso-occlusion or chronic vasculopathy. Applying concepts of systems biology and network medicine, models were developed to show relationships between the primary defect of sickle hemoglobin (Hb S) polymerization and the outcomes of acute pain and chronic vasculopathy. Pathophysiologic processes such as inflammation and oxidative stress are downstream by-products of Hb S polymerization, transduced through secondary pathways of hemolysis and vaso-occlusion. Pain, a common clinical trials endpoint, is also complex and may be influenced by factors outside of sickle cell polymerization and vascular occlusion. Future sickle cell research needs to better address the biologic complexity of both sickle cell disease and pain. The relevance of individual pathways to important sickle cell outcomes needs to be demonstratedin vivobefore investing in expensive and labor-intensive clinical trials.

scholarly journals Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1544
Author(s):  
Sonia Saib ◽  
Xavier Delavenne
Keyword(s):  
Abc Transporters ◽  
Drug Exposure ◽  
Drug Disposition ◽  
Therapeutic Index ◽  
Functional Expression ◽  
In Vivo Models ◽  
Inflammatory Conditions ◽  
Transporter Expression

The ATP-binding cassette (ABC) transporters play a key role in drug pharmacokinetics. These membrane transporters expressed within physiological barriers can be a source of pharmacokinetic variability. Changes in ABC transporter expression and functionality may consequently affect the disposition of substrate drugs, resulting in different drug exposure. Inflammation, present in several acute and chronic diseases, has been identified as a source of modulation in drug transporter expression leading to variability in drug response. Its regulation may be particularly dangerous for drugs with a narrow therapeutic index. In this context, numerous in vitro and in vivo models have shown up- or downregulation in the expression and functionality of ABC transporters under inflammatory conditions. Nevertheless, the existence of contradictory data and the lack of standardization for the models used have led to a less conclusive interpretation of these data.

scholarly journals In Vivo Targeting of CXCR4—New Horizons

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5920
Author(s):  
Margret Schottelius ◽  
Ken Herrmann ◽  
Constantin Lapa
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Clinical Status ◽  
Inflammatory Stimuli ◽  
Imaging Probes ◽  
Recent Developments ◽  
Chemokine Receptor 4

Given its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) has attracted a lot of interest in the field of nuclear oncology, and clinical evidence on the high potential of CXCR4-targeted theranostics is constantly accumulating. Additionally, since CXCR4 also represents a key player in the orchestration of inflammatory responses to inflammatory stimuli, based on its expression on a variety of pro- and anti-inflammatory immune cells (e.g., macrophages and T-cells), CXCR4-targeted inflammation imaging has recently gained considerable attention. Therefore, after briefly summarizing the current clinical status quo of CXCR4-targeted theranostics in cancer, this review primarily focuses on imaging of a broad spectrum of inflammatory diseases via the quantification of tissue infiltration with CXCR4-expressing immune cells. An up-to-date overview of the ongoing preclinical and clinical efforts to visualize inflammation and its resolution over time is provided, and the predictive value of the CXCR4-associated imaging signal for disease outcome is discussed. Since the sensitivity and specificity of CXCR4-targeted immune cell imaging greatly relies on the availability of suitable, tailored imaging probes, recent developments in the field of CXCR4-targeted imaging agents for various applications are also addressed.

scholarly journals Macrophage Inflammatory Protein 3α Is Expressed at Inflamed Epithelial Surfaces and Is the Most Potent Chemokine Known in Attracting Langerhans Cell Precursors

2000 ◽  
Vol 192 (5) ◽  
pp. 705-718 ◽  
Author(s):  
Marie-Caroline Dieu-Nosjean ◽  
Catherine Massacrier ◽  
Bernhard Homey ◽  
Béatrice Vanbervliet ◽  
Jean-Jacques Pin ◽  
...  
Keyword(s):  
Hematopoietic Progenitor Cell ◽  
Psoriatic Skin ◽  
Inflammatory Conditions ◽  
Inflammatory Protein ◽  
Inflammatory Stimuli ◽  
Epithelial Immunity ◽  
Factor Α ◽  
Macrophage Inflammatory Protein

Dendritic cells (DCs) form a network comprising different populations that initiate and differentially regulate immune responses. Langerhans cells (LCs) represent a unique population of DCs colonizing epithelium, and we present here observations suggesting that macrophage inflammatory protein (MIP)-3α plays a central role in LC precursor recruitment into the epithelium during inflammation. (a) Among DC populations, MIP-3α was the most potent chemokine inducing the selective migration of in vitro–generated CD34+ hematopoietic progenitor cell–derived LC precursors and skin LCs in accordance with the restricted MIP-3α receptor (CC chemokine receptor 6) expression to these cells. (b) MIP-3α was mainly produced by epithelial cells, and the migration of LC precursors induced by the supernatant of activated skin keratinocytes was completely blocked with an antibody against MIP-3α. (c) In vivo, MIP-3α was selectively produced at sites of inflammation as illustrated in tonsils and lesional psoriatic skin where MIP-3α upregulation appeared associated with an increase in LC turnover. (d) Finally, the secretion of MIP-3α was strongly upregulated by cells of epithelial origin after inflammatory stimuli (interleukin 1β plus tumor necrosis factor α) or T cell signals. Results of this study suggest a major role of MIP-3α in epithelial colonization by LCs under inflammatory conditions and immune disorders, and might open new ways to control epithelial immunity.

scholarly journals Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection

2018 ◽  
Vol 215 (4) ◽  
pp. 1035-1045 ◽  
Author(s):  
Sharmila Nair ◽  
Jeremy P. Huynh ◽  
Vicky Lampropoulou ◽  
Ekaterina Loginicheva ◽  
Ekaterina Esaulova ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Conditional Knockout ◽  
Transcriptional Level ◽  
Inhibitory Effects ◽  
Culture Studies ◽  
Inflammatory Conditions ◽  
Neutrophil Depletion ◽  
Species Production

Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1−/− mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1−/−, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.

scholarly journals In Vivo Motility Patterns Displayed by Immune Cells Under Inflammatory Conditions

2022 ◽  
Vol 12 ◽  
Author(s):  
Diego Ulisse Pizzagalli ◽  
Alain Pulfer ◽  
Marcus Thelen ◽  
Rolf Krause ◽  
Santiago F. Gonzalez
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Intravital Microscopy ◽  
Interdisciplinary Approach ◽  
Imaging Data ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli ◽  
Living Organisms ◽  
Comprehensive Classification

The migration of immune cells plays a key role in inflammation. This is evident in the fact that inflammatory stimuli elicit a broad range of migration patterns in immune cells. Since these patterns are pivotal for initiating the immune response, their dysregulation is associated with life-threatening conditions including organ failure, chronic inflammation, autoimmunity, and cancer, amongst others. Over the last two decades, thanks to advancements in the intravital microscopy technology, it has become possible to visualize cell migration in living organisms with unprecedented resolution, helping to deconstruct hitherto unexplored aspects of the immune response associated with the dynamism of cells. However, a comprehensive classification of the main motility patterns of immune cells observed in vivo, along with their relevance to the inflammatory process, is still lacking. In this review we defined cell actions as motility patterns displayed by immune cells, which are associated with a specific role during the immune response. In this regard, we summarize the main actions performed by immune cells during intravital microscopy studies. For each of these actions, we provide a consensus name, a definition based on morphodynamic properties, and the biological contexts in which it was reported. Moreover, we provide an overview of the computational methods that were employed for the quantification, fostering an interdisciplinary approach to study the immune system from imaging data.

INTERACTION OF CD44 AND HYALURONAN IS THE DOMINANT MECHANISM FOR NEUTROPHIL ADHESION IN INFLAMED LIVER SINUSOIDS

2008 ◽  
Vol 31 (4) ◽  
pp. 16
Author(s):  
Braedon McDonald ◽  
Erin F McAvoy ◽  
Florence Lam ◽  
Varinder Gill ◽  
Paul Kubes
Keyword(s):  
Adhesion Molecules ◽  
Intravital Microscopy ◽  
Inflammatory Responses ◽  
Flow Chamber ◽  
Neutrophil Recruitment ◽  
Neutrophil Adhesion ◽  
Antibody Technique ◽  
Liver Sinusoids

Background: Previous studies have been unable to identify adhesion molecules that mediate neutrophil recruitment within the liver sinusoids. We hypothesise that involved adhesion molecules may represent novel therapeutic targets for combating pathologic liver inflammation. Methods: Candidate adhesion molecules were identified using a novel in vivo biopanning approach (dual radiolabelled antibody technique) to quantify endothelial expression levels within the liver compared to other organs. Spinning disk intravital microscopy demonstrated the localization of adhesion molecule expression withinthe liver microvasculature. Using knockout mice, bone marrow chimeric mice, and blocking antibodies, candidate adhesion molecules were systematically investigated for a role in neutrophil recruitment in the liver sinusoids of endotoxemic mice using intravital microscopy and in vitro flow chamber assays. Results: Hyaluronan was identified as disproportionately expressed in the liver versus other organs, and hyaluronan expression was restricted to liver sinusoids. Blocking CD44-hyaluronan interactions reduced neutrophil adhesion in the sinusoids of endotoxemic mice, but had no effect on neutrophil rolling or adhesion in post-sinusoidal venules. Neutrophil but not endothelial CD44 was required for adhesionin sinusoids. Surprisingly, neutrophil CD44 avidity for hyaluronan was not increased in endotoxemia. Instead, activation of CD44-hyaluronan engagement was the result of qualitative modification of hyaluronan by a dramatic induction of serum-derived hyaluronan-associated protein (SHAP) in sinusoids in response to lipopolysaccharide. Lipopolysaccharide-induced hepatic injury was significantly reduced by inhibiting CD44-hyaluronan interactions. Therapeutic administration of anti-CD44 antibody to endotoxemic mice rapidly detached adherent neutrophils and improved sinusoidal perfusion. Conclusion: These findings reveal CD44 as a potential therapeutic target in systemic inflammatory responses involving liver.

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