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.

Lung epithelial NOX/DUOX and respiratory virus infections

2014 ◽  
Vol 128 (6) ◽  
pp. 337-347 ◽  
Author(s):  
Nathalie Grandvaux ◽  
Mélissa Mariani ◽  
Karin Fink
Keyword(s):  
Respiratory Virus ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Conditional Knockout ◽  
In Vivo Studies ◽  
Virus Infections ◽  
Lung Epithelial ◽  
Respiratory Virus Infections

Determining the role of NADPH oxidases in the context of virus infection is an emerging area of research and our knowledge is still sparse. The expression of various isoforms of NOX/DUOX (NADPH oxidase/dual oxidase) in the epithelial cells (ECs) lining the respiratory tract renders them primary sites from which to orchestrate the host defence against respiratory viruses. Accumulating evidence reveals distinct facets of the involvement of NOX/DUOX in host antiviral and pro-inflammatory responses and in the control of the epithelial barrier integrity, with individual isoforms mediating co-operative, but surprisingly also opposing, functions. Although in vivo studies in mice are in line with some of these observations, a complete understanding of the specific functions of epithelial NOX/DUOX awaits lung epithelial-specific conditional knockout mice. The goal of the present review is to summarize our current knowledge of the role of individual NOX/DUOX isoforms expressed in the lung epithelium in the context of respiratory virus infections so as to highlight potential opportunities for therapeutic intervention.

scholarly journals In Vivo Anti-Inflammation Potential of Aster koraiensis Extract for Dry Eye Syndrome by the Protection of Ocular Surface

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3245
Author(s):  
Sung-Chul Hong ◽  
Jung-Heun Ha ◽  
Jennifer K. Lee ◽  
Sang Hoon Jung ◽  
Jin-Chul Kim
Keyword(s):  
Animal Model ◽  
Er Stress ◽  
Dry Eye ◽  
Lacrimal Gland ◽  
Ocular Surface ◽  
Inflammatory Responses ◽  
Dry Eye Syndrome ◽  
Inhibitory Effects ◽  
Food Material

Dry eye syndrome (DES) is a corneal disease often characterized by an irritating, itching feeling in the eyes and light sensitivity. Inflammation and endoplasmic reticulum (ER) stress may play a crucial role in the pathogenesis of DES, although the underlying mechanism remains elusive. Aster koraiensis has been used traditionally as an edible herb in Korea. It has been reported to have wound-healing and inhibitory effects against insulin resistance and inflammation. Here, we examined the inhibitory effects of inflammation and ER stress by A. koraiensis extract (AKE) in animal model and human retinal pigmented epithelial (ARPE-19) cells. Oral administration of AKE mitigated DE symptoms, including reduced corneal epithelial thickness, increased the gap between lacrimal gland tissues in experimental animals and decreased tear production. It also inhibited inflammatory responses in the corneal epithelium and lacrimal gland. Consequently, the activation of NF-κB was attenuated by the suppression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Moreover, AKE treatment ameliorated TNF-α-inducible ocular inflammation and thapsigargin (Tg)-inducible ER stress in animal model and human retinal pigmented epithelial (ARPE-19) cells. These results prove that AKE prevents detrimental functional and histological remodeling on the ocular surface and in the lacrimal gland through inhibition of inflammation and ER stress, suggesting its potential as functional food material for improvement of DES.

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 Neutrophil-specific deletion of Syk kinase results in reduced host defense to bacterial infection

Blood ◽  
2009 ◽  
Vol 114 (23) ◽  
pp. 4871-4882 ◽  
Author(s):  
Jessica A. Van Ziffle ◽  
Clifford A. Lowell
Keyword(s):  
Bacterial Infection ◽  
Host Defense ◽  
Myeloid Cells ◽  
Inflammatory Cells ◽  
Defense Responses ◽  
Conditional Knockout ◽  
Neutrophil Extracellular Trap ◽  
Integrin Signaling ◽  
Syk Kinase

Abstract Leukocyte-specific CD18 integrins are critical in mediating cell recruitment and activation during host defense responses to bacterial infection. The signaling pathways downstream of CD18 integrins are dependent on the spleen tyrosine kinase, Syk. To investigate the role integrin signaling plays in host defense, we examined the responses of Syk-deficient neutrophils to bacterial challenge with serum-opsonized Staphylococcus aureus and Escherichia coli. Syk-conditional knockout mice lacking this kinase specifically in myeloid cells or just neutrophils were also used to investigate host responses in vivo. Syk-deficient neutrophils manifested impaired exocytosis of secondary and tertiary granules, reduced cytokine release, and very poor activation of the NADPH oxidase in response to serum-opsonized S aureus and E coli. These functional defects correlated with impaired activation of c-Cbl, Pyk2, Erk1/2, and p38 kinases. Bacterial phagocytosis, neutrophil extracellular trap formation, and killing were also reduced in Syk-deficient cells, with a more profound effect after S aureus challenge. In vivo, loss of Syk in myeloid cells or specifically in neutrophils resulted in reduced clearance of S aureus after subcutaneous or intraperitoneal infection, despite normal recruitment of inflammatory cells. These results indicate that loss of Syk kinase-mediated integrin signaling impairs leukocyte activation, leading to reduced host defense responses.

scholarly journals The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells

2009 ◽  
Vol 206 (3) ◽  
pp. 623-635 ◽  
Author(s):  
Luigi Maddaluno ◽  
Sue Ellen Verbrugge ◽  
Chiara Martinoli ◽  
Gianluca Matteoli ◽  
Andrea Chiavelli ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Adhesion Molecule ◽  
Vascular Endothelium ◽  
Langerhans Cells ◽  
Transendothelial Migration ◽  
Conditional Knockout ◽  
Inflammatory Conditions ◽  
Draining Lymph Nodes ◽  
Shed Light

The adhesion molecule L1, which is extensively characterized in the nervous system, is also expressed in dendritic cells (DCs), but its function there has remained elusive. To address this issue, we ablated L1 expression in DCs of conditional knockout mice. L1-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1 in transendothelial migration of DCs. In agreement with these findings, L1 was expressed in cutaneous DCs that migrated to draining lymph nodes, and its ablation reduced DC trafficking in vivo. Within the skin, L1 was found in Langerhans cells but not in dermal DCs, and L1 deficiency impaired Langerhans cell migration. Under inflammatory conditions, L1 also became expressed in vascular endothelium and enhanced transmigration of DCs, likely through L1 homophilic interactions. Our results implicate L1 in the regulation of DC trafficking and shed light on novel mechanisms underlying transendothelial migration of DCs. These observations might offer novel therapeutic perspectives for the treatment of certain immunological disorders.

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.

In Vivo Visualization of Stat3 Activation in Myeloid Cells during Inflammation and Tumor Growth.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3434-3434
Author(s):  
Pedro Horna ◽  
Fengdong Cheng ◽  
Richard Jove ◽  
Linda Mora ◽  
Eduardo M. Sotomayor
Keyword(s):  
Steady State ◽  
Immune Responses ◽  
Tumor Growth ◽  
Peripheral Blood ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Tumor Bearing ◽  
Inflammatory Site ◽  
Number Of Cells

Abstract Signal transducer and activator of transcription 3 (Stat3) is a key mediator of several cytokine and growth factor signaling pathways. On myeloid cells, activation of Stat3 to its phosphorylated form (pStat3) has been shown to negatively regulate inflammatory responses and play a central role in the decision leading to immune activation versus immune tolerance of antigen-specific T-cells1. Little is still known however, about the status of Stat3 signaling in myeloid cells in the steady state and during ongoing immune responses in vivo. To address this question we recently developed flow-cytometric and immuno-histochemistry assays that have allowed us to visualize the in vivo dynamics of Stat3 activation in myeloid cells during immune responses leading to divergent outcomes: productive inflammatory response to adjuvant immunization and tumor-induced unresponsiveness or tolerance. In the steady state we found that in peripheral blood only Ly6G+ polymorphonuclear cells display a positive nuclear staining for pStat3. Analysis of lymphoid organs revealed that although Stat3 protein was expressed almost ubiquitously on spleen sections of normal mice, only a small number of cells were positive for pStat3. Following immunization with complete Freund adjuvant (CFA) a dramatic increase in the number of cells expressing pStat3 was observed in the peripheral blood and spleen of treated animals. Ly6G+ pStat3+ were rapidly recruited from the blood to the inflammatory site where they now displayed significantly decreased levels of pStat3. During the growth of a subcutaneous tumor, a similar increase in the number of cells expressing pStat3 was observed in the blood and spleen of tumor-bearing mice. Further analysis by flow cytometry revealed that pStat3 expression was restricted to two sub-populations: a) CD11b+ myeloid cells expressing the lineage marker Gr-1 and b) Ly6G− mononuclear cells unable to down-regulate Stat3 activity following their migration from the blood into peripheral tissues. In vivo depletion of Gr-1+ cells eliminated most of the pStat3+ cells in tumor bearing mice. The immunoregulatory properties of these Gr-1+ cells was highlighted by the demonstration that in their absence, in vivo immunization with a peptide derived from influenza hemagglutinin (HA) in CFA markedly enhanced the priming of anti-HA specific CD4+ T-cells. More importantly, in animals depleted of Gr-1+ cells, the outcome in response to a tolerogenic stimuli was T-cell activation rather than tolerance induction. Taken together, although similar changes in the number of cells expressing pStat3 was observed in response to adjuvant immunization and during tumor progression, an important difference might relate to the extent of Stat3 activation in myeloid cells following their migration to the site of stimuli. While down-regulation of Stat3 in myeloid cells at the inflammatory site is an early event during productive inflammatory responses, a sustained Stat3 activation in myeloid cells such as that observed during tumor growth may provide an explanation for the state of immune unresponsiveness associated with malignancies.

Mechanisms of Synergy Between Toll-Like Receptor 4 and Triggering Receptor Expressed on Myeloid Cells-1 in Human Neutrophils

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3547-3547
Author(s):  
Markus P Radsak ◽  
Hansjörg Schild ◽  
Philipp Haselmayer ◽  
Helmut R Salih
Keyword(s):  
Respiratory Burst ◽  
Transient Receptor Potential ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Polymorphonuclear Neutrophils ◽  
Human Neutrophils ◽  
Inflammatory Conditions ◽  
Potential Channels

Abstract The triggering receptor expressed on myeloid cells 1 (TREM-1) is an important player in the innate inflammatory response to microbial infections. Activation and expression of TREM-1 by polymorphonuclear neutrophils (PMN) occurs in concert with Toll-like receptors (TLR) such as TLR4 for bacterial lipopolysaccharide. However, it is currently unclear how this is mediated on a molecular level. Using pharmacologic inhibitors and western blot analysis we demonstrate that phosphatidyl inositide 3-kinase, phospholipase C and the mitogen activated kinase p38 are essential for the TREM-1 and TLR4 mediated respiratory burst of human PMN. The down stream phosphorylation of protein kinase B and extracellular signal related kinase show characteristic phosphorylation patterns upon single or co-ligation indicating individual activation pathways of both receptors. TREM-1, but not TLR4 mediated respiratory burst depended on calcium flow via store operated calcium entry channels, while transient receptor potential channels were important for TLR and TREM-1. Taken together, we provide new insights on the mechanisms how TREM-1 and TLR interact creating synergistic activation in PMN. These results shed a new light on our understanding how the innate inflammatory responses are regulated and might contribute to the development of future concepts for the treatment of severe inflammatory conditions such as sepsis.

scholarly journals Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells

2013 ◽  
Vol 74 (1) ◽  
pp. 227-233 ◽  
Author(s):  
Stephan Blüml ◽  
Martin Friedrich ◽  
Tobias Lohmeyer ◽  
Emine Sahin ◽  
Victoria Saferding ◽  
...  
Keyword(s):  
Myeloid Cells ◽  
Bone Destruction ◽  
Precursor Cells ◽  
Nuclear Factor ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Inflammatory Conditions ◽  
Local Bone

ObjectiveLocal bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions.MethodsWe analysed osteoclastogenesis of wildtype (wt) and PTEN−/− cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model.ResultsWe show that myeloid-specific PTEN−/− mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN−/− mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN−/− mice.ConclusionsThese data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.

scholarly journals CXCR2 deficient mice display macrophage-dependent exaggerated acute inflammatory responses

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Douglas P. Dyer ◽  
Kenneth Pallas ◽  
Laura Medina-Ruiz ◽  
Fabian Schuette ◽  
Gillian J. Wilson ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Inflammatory Stimuli ◽  
Neutrophil Depletion ◽  
Deficient Mice ◽  
Important Therapeutic Target ◽  
Macrophage Accumulation

Abstract CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response.

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