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| Open AccessN-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis
In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
- Mausita Karmakar
- , Martin Minns
- & Eric Pearlman
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Article
| Open AccessThe platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure
The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.
- Abhishek Chauhan
- , Lozan Sheriff
- & Patricia F. Lalor
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| Open AccessNeutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis
Antimicrobial peptide LL37 can bind nucleic acids and potentiate their sensing by endosomal TLRs. Here the authors show that LL37 binds to RNA from neutrophil extracellular traps (NETs), which amplifies inflammation and production of more LL37 and NETs via TLR8/13, suggesting that LL37 contribution to psoriasis may be fueled by NET-associated RNA.
- Franziska Herster
- , Zsofia Bittner
- & Alexander N. R. Weber
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Article
| Open AccessChemokine receptor trafficking coordinates neutrophil clustering and dispersal at wounds in zebrafish
Inflammatory responses must be induced and resolved timely to serve protection from pathogens without inducing excessive tissue damage. Here the authors use live imaging in zebrafish to show that the intracellular trafficking of two chemokine receptors, Cxcr1 and Cxcr2, is differentially regulated on activated neutrophils to control their clustering and dispersal, respectively.
- Caroline Coombs
- , Antonios Georgantzoglou
- & Milka Sarris
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Article
| Open AccessAdenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome
Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.
- Ramadan A. Ali
- , Alex A. Gandhi
- & Jason S. Knight
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| Open AccessThe role of platelets in mediating a response to human influenza infection
Influenza viremia is rare in human blood and not well studied. Here, the authors show that influenza can be found in human platelets and that platelet engulfment of influenza A results in TLR7-dependent C3 release, which in turn promotes neutrophil-DNA release and formation of platelet-DNA aggregates.
- Milka Koupenova
- , Heather A. Corkrey
- & Jane E. Freedman
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| Open AccessNeutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis
Neutrophils play critical roles in the host response to bacteria, including the production neutrophil extracellular traps (NET). Here the authors show that NET formation in the context of pneumococcal meningitis impairs bacterial clearance and targeting NET formation in this context could be a potential therapeutic option.
- Tirthankar Mohanty
- , Jane Fisher
- & Adam Linder
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| Open AccessNeutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
The pathogenesis of heparin-induced thrombocytopenia and thrombosis (HIT) is mediated by heparin-reactive autoantibodies binding to platelets (thrombocytes). Here the authors show neutrophil activation and NETosis are elevated in patients with HIT, and are essential for thrombosis in HIT mouse models.
- José Perdomo
- , Halina H. L. Leung
- & Beng H. Chong
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Article
| Open AccessNeutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair
Neutrophils and macrophages are both involved in the initiation of inflammation, but whether and how they may participate in inflammation resolution is unclear. Here the authors show that neutrophils may mediate the conversion of macrophage into a pro-resolution phenotype via reactive oxygen species production to promote liver repair.
- Wenting Yang
- , Yuandong Tao
- & Li Tang
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Article
| Open AccessJapanese encephalitis virus neuropenetrance is driven by mast cell chymase
How Japanese encephalitis virus (JEV) penetrates the blood-brain barrier (BBB) remains unclear. Here, using a genetic mouse model and a virulent JEV strain, the authors show that perivascular mast cells (MC) mediate JEV neuroinvasion and identify the MC-protease chymase as a potential therapeutic target.
- Justin T. Hsieh
- , Abhay P. S. Rathore
- & Ashley L. St. John
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Article
| Open AccessTumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
Neutrophils normally fulfil their metabolic demands by glycolysis and have limited mitochondrial activity. Here the authors show that tumours promote neutrophils adapted to oxidative mitochondria metabolism that function in the glucose-restrained tumour microenvironment to promote tumour growth by maintaining local immune suppression.
- Christopher M. Rice
- , Luke C. Davies
- & Daniel W. McVicar
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| Open AccessPlasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis
Neutrophil extracellular traps (NETs) are known to promote metastasis in mouse models. Here the authors show plasma redox imbalance caused by albumin oxidation to induce inflammation-independent NETosis and lung metastasis, and albumin oxidation and reduced plasma free thiol to be associated with lung metastasis in a cohort of head and neck cancer patients.
- Minoru Inoue
- , Ryota Nakashima
- & Scott V. Bratman
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Article
| Open AccessCis interaction between sialylated FcγRIIA and the αI-domain of Mac-1 limits antibody-mediated neutrophil recruitment
Deposited immune complexes (IC) promote neutrophil recruitment, but the fine tuning of this process is still unclear. Here the authors show that the cis interaction of the IC receptor, FcγRIIA and CD18 integrin, Mac-1, on the neutrophil surface modulates neutrophil adhesion, with FcγRIIA sialylation specifically implicated in this interaction.
- Gurpanna Saggu
- , Koshu Okubo
- & Tanya N. Mayadas
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Article
| Open AccessEosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge
Eosinophils are important mediators of allergic responses, but how they are recruited to the inflamed site is still unclear. Here the authors show that CD103+ cDC1 cells secrete CCL17 and CCL22 for eosinophil recruitment, with this process promoted by CD24−CD11b+ DC2s in the early phase but suppressed by CD24+ cDC2s in the late phase.
- Shuying Yi
- , Jing Zhai
- & Hua Tang
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Article
| Open AccessEndogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase
Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.
- Helmut Pein
- , Alexia Ville
- & Andreas Koeberle
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Article
| Open AccessChromatin swelling drives neutrophil extracellular trap release
Neutrophilic granulocytes release their own DNA (NETosis) as neutrophil extracellular traps to capture pathogens. Here, the authors use time-resolved fluorescence and atomic force microscopy and reveal that NETosis is highly organized into three distinct phases with a clear point of no return defined by chromatin status.
- Elsa Neubert
- , Daniel Meyer
- & Sebastian Kruss
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| Open AccessNAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease
Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent inflammasome activation in neutrophils contributes to systemic inflammation.
- Randilea D. Nichols
- , Jakob von Moltke
- & Russell E. Vance
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| Open AccessNeutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage
Neutrophils are important modulators of tissue damage after intracerebral hemorrhage (ICH), but how this function is regulated is not clear. Here, the authors show interleukin-27 promotes the tissue-protecting functions of neutrophils via, at least partly, the induction of lactoferrin to present a potential therapy for ICH.
- Xiurong Zhao
- , Shun-Ming Ting
- & Jaroslaw Aronowski
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| Open AccessExploiting a novel conformational switch to control innate immunity mediated by complement protein C3a
Complement C3a is an important protein in innate and adaptive immunity, but its roles in vivo are unclear. Here the authors develop novel chemical agonists and antagonists for the C3a receptor, and show that they modulate mast cell degranulation and inflammation in a rat paw edema model
- Rink-Jan Lohman
- , Johan K. Hamidon
- & David P. Fairlie
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| Open AccessDEK-targeting DNA aptamers as therapeutics for inflammatory arthritis
DEK is a secreted protein abundant in the synovia of patients with juvenile idiopathic arthritis. Here the authors show DEK is important for neutrophil extracellular trap formation and joint inflammation, and demonstrate therapeutic efficacy of DEK-targeting aptamers in a mouse model of arthritis.
- Nirit Mor-Vaknin
- , Anjan Saha
- & David M. Markovitz
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| Open AccessDirected transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response
Interaction between platelets and neutrophils promotes neutrophil activation. Here the authors show that neutrophils initiate the cross-talk with platelets by shuttling arachidonic acid via extracellular vesicles, which platelets convert to thromboxane A2that then elicits neutrophil activation.
- Jan Rossaint
- , Katharina Kühne
- & Alexander Zarbock
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| Open AccessNeutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis
Integrin β2 attachment regulates inflammation via effects on neutrophil rolling and extravasation through sequential integrin extension then headpiece opening. Here the authors show an alternative open headpiece prior to extension stabilized in cisby ICAM-1 that limits neutrophil adhesion.
- Zhichao Fan
- , Sara McArdle
- & Klaus Ley
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| Open AccessNeutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins
The role of guanylate-binding proteins (GBPs) in innate immunity is increasingly recognized. Here the authors show that GBP4 activates inflammasome in zebrafish neutrophils, and that this process is critical for the clearance of Salmonellainfection via prostaglandin D2.
- Sylwia D. Tyrkalska
- , Sergio Candel
- & Victoriano Mulero
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| Open AccessTh2 and eosinophil responses suppress inflammatory arthritis
Type 2 immune responses are viewed as opposites of Type 1 and 17 responses. Here the authors show that activation of Type 2 immunity by helminth infection counteracts the development of inflammatory arthritis, a type 17-mediated pathology, via IL-4/IL-13- STAT6 signalling and eosinophil activation.
- Zhu Chen
- , Darja Andreev
- & Aline Bozec
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Article
| Open AccessNETosis and lack of DNase activity are key factors in Echis carinatus venom-induced tissue destruction
The saw-scaled viper venom causes continued tissue damage that may cause death. Here the authors show that the venom attracts neutrophils to the bite site and induces neutrophil extracellular traps that capture venom components causing tissue damage, which can be prevented by enzymatic DNA degradation.
- Gajanan D. Katkar
- , Mahalingam S. Sundaram
- & Kempaiah Kemparaju
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| Open AccessNeutrophil-specific deletion of the CARD9 gene expression regulator suppresses autoantibody-induced inflammation in vivo
Neutrophils play an important role in antimicrobial host defence but can also contribute to non-infectious inflammatory processes. Here the authors show that adaptor protein CARD9 expressed in neutrophils is involved in the development of sterile auto-antibody-mediated inflammatory reactions.
- Tamás Németh
- , Krisztina Futosi
- & Attila Mócsai
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| Open AccessCoagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis
It is unclear whether cancer-related hypercoagulation and neutrophilia contribute to tumorigenesis. In this study, the authors find that activation of the complement cascade causes hypercoagulation that leads to polarization of neutrophils in a mouse model of intestinal cancer, and show that blocking complement activation can reduce tumour formation.
- Silvia Guglietta
- , Andrea Chiavelli
- & Maria Rescigno
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| Open AccessExternalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis
Pancreatitis often develops as a consequence of ductal obstruction. Here, the authors show that bicarbonate ions initiate the release of neutrophil extracellular traps (NETs) that form pancreatic ductal aggregates and occlude the ducts, thereby driving pancreatitis in mice and humans.
- Moritz Leppkes
- , Christian Maueröder
- & Christoph Becker
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| Open AccessProtection from septic peritonitis by rapid neutrophil recruitment through omental high endothelial venules
Neutrophils are critical in preventing the transition of acute peritoneal infection to sepsis. Here the authors show in three mouse models of peritonitis that neutrophils enter the abdominal cavity via high endothelial venules of the greater omentum, and characterize adhesion molecules involved.
- Konrad Buscher
- , Huiyu Wang
- & Jian Song
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Article
| Open AccessSocial amoebae trap and kill bacteria by casting DNA nets
Neutrophils secrete net-like structures made of DNA and anti-microbial peptides, which can trap and kill extracellular pathogens. Here, the authors show that such nets are also produced by so-called Sentinel cells in the multicellular slug stage of the social amoeba Dictyostelium discoideum.
- Xuezhi Zhang
- , Olga Zhuchenko
- & Thierry Soldati
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| Open AccessNeutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP
Neutrophils are a major source of IL-1 β in a number of inflammatory settings. Here the authors show that mouse and human neutrophils express functional P2X7 receptors, which mediate ATP-triggered NLRP3 inflammasome activation and IL-1 ß secretion.
- Mausita Karmakar
- , Michael A. Katsnelson
- & Eric Pearlman
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Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide
Tamoxifen, widely used to modulate oestrogen receptor activity in breast cancer treatment, also regulates sphingolipid metabolism. Here the authors show that the latter activity of tamoxifen stimulates pro-inflammatory and antibacterial activities of human neutrophils.
- Ross Corriden
- , Andrew Hollands
- & Victor Nizet
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| Open AccessGenome-wide analysis of the genetic regulation of gene expression in human neutrophils
Neutrophils are abundant immune cells important for antimicrobial defence and in autoimmunity. Here, by mapping expression quantitative trait loci (eQTL) in neutrophils of Chinese ethnicity from Singapore, Andiappan et al.provide a resource for understanding immune-related trait associated genetic variants.
- Anand Kumar Andiappan
- , Rossella Melchiotti
- & Olaf Rotzschke
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PGD2 deficiency exacerbates food antigen-induced mast cell hyperplasia
Mast cells are major contributors to allergy. Here the authors show that prostaglandin D2-deficient mast cells produce more chemoattractants, promoting mast cell hyperplasia and exacerbating allergic responses in a mouse model of food allergy.
- Tatsuro Nakamura
- , Shingo Maeda
- & Takahisa Murata
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| Open AccessGenetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study
Graves’ disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
- Pei-Lung Chen
- , Shyang-Rong Shih
- & Tien-Chun Chang
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| Open AccessGenomic modulators of gene expression in human neutrophils
Neutrophils are the most abundant subset of leukocyte and central to many diseases. Here by mapping expression quantitative trait loci (eQTL) in the context of epigenetic marks in neutrophils and monocytes of 101 healthy European adults, the authors provide a resource to advance understanding of immune-related trait-associated genetic variants.
- Vivek Naranbhai
- , Benjamin P. Fairfax
- & Julian C. Knight
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The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing
Neutrophils are the first line of response to injury but their persistence can inhibit the resolution phase of tissue repair. Here the authors show that an extracellular matrix protein promotes neutrophil clearance by macrophages, serving as a bridge between the two cell types and speeding up tissue repair.
- Joon-Il Jun
- , Ki-Hyun Kim
- & Lester F. Lau
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Article
| Open AccessMicrobe-dependent lymphatic migration of neutrophils modulates lymphocyte proliferation in lymph nodes
Both sterile and microbial injuries lead to rapid neutrophil recruitment to the site of inflammation. Here the authors show that only neutrophils responding to microbial ligands leave inflamed skin and migrate to draining lymph nodes where they stimulate lymphocyte proliferation.
- Henry R. Hampton
- , Jacqueline Bailey
- & Tatyana Chtanova
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Interplay between enterobactin, myeloperoxidase and lipocalin 2 regulates E. coli survival in the inflamed gut
Gut inflammation triggers a bloom of certain resident bacteria such as E. coli that can contribute to disease. Here, Singh et al. show that a siderophore produced by E. coliinhibits the antibacterial activity of host myeloperoxidase and enhances bacterial survival in the gut of lab mice.
- Vishal Singh
- , Beng San Yeoh
- & Matam Vijay-Kumar
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Article
| Open AccessExtracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion
MRP8/14 are actively secreted by myeloid cells during inflammation. Here the authors show that MRP8/14 play an important role in leukocyte recruitment to the inflammatory site, triggering an autocrine cascade that promotes neutrophil adhesion to the endothelium.
- Monika Pruenster
- , Angela R. M. Kurz
- & Markus Sperandio
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Article
| Open AccessNFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma
The role of neutrophils in cancer development is not widely appreciated. Here, the authors show that NF-κB-deficient hepatocytes overproduce chemokines, leading to hepatocellular carcinoma due to excessive neutrophil recruitment, and that neutrophil depletion prevents liver cancer in these mice.
- C. L. Wilson
- , D. Jurk
- & D. A. Mann
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| Open AccessMolecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature
Neutrophil extracellular traps (NETs) released by neutrophils trap pathogens but may also cause tissue damage. Here the authors show that during systemic Staphylococcus aureusinfection NETs anchoring to the vasculature are only partially DNase-sensitive, advocating for better anti-NET therapies.
- Elzbieta Kolaczkowska
- , Craig N. Jenne
- & Paul Kubes
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Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence
Mast cells are tissue-resident immune cells important for clearance of parasitic worms but also mediating allergic reactions. Here Joulia et al. show that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens to increase efficiency and minimize off-target effects.
- Régis Joulia
- , Nicolas Gaudenzio
- & Eric Espinosa
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Chromatin remodelling and autocrine TNFα are required for optimal interleukin-6 expression in activated human neutrophils
How IL-6 expression is regulated in human neutrophils has remained unclear. Here the authors show, using highly purified neutrophils, that TLR8 or TLR4 signalling activates latent enhancers and cooperates with autocrine TNFα to induce IL-6transcription.
- Maili Zimmermann
- , Francisco Bianchetto Aguilera
- & Marco A. Cassatella
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Article
| Open AccessOncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation
Activating mutations of the tyrosine kinase Kit are commonly found in mast cell neoplasms and gastrointestinal stromal tumours. Here the authors show that mutant Kit, through the activation of PI3K and STAT3 pathways, elicits proliferative and survival signals from endolysosomes and from the endoplasmic reticulum.
- Yuuki Obata
- , Shota Toyoshima
- & Ryo Abe
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IRF8 inhibits C/EBPα activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils
The mechanisms mediating lineage restriction in haematopoietic cell differentiation are not well understood. Here the authors show when and how the transcription factor IRF8 inhibits neutrophil differentiation during the lineage selection of monocytes and dendritic cells.
- Daisuke Kurotaki
- , Michio Yamamoto
- & Tomohiko Tamura
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ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48
ORMDL3has been identified as a gene associated with asthma susceptibility, but its exact role in the pathogenesis of this disease is not well known. Here, the authors propose that induction of ORMDL3 in eosinophils modulates the expression of integrins, which could contribute to a key inflammatory event in asthma.
- Sung Gil Ha
- , Xiao Na Ge
- & P. Sriramarao
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Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state
SIRPα is an anti-inflammatory signalling receptor expressed on neutrophils. Here Zenet al.show that during inflammation, SIRPα signalling is inhibited by cleavage of its intracellular signalling motif.
- Ke Zen
- , Yalan Guo
- & Yuan Liu
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| Open AccessBasophils are required for the induction of Th2 immunity to haptens and peptide antigens
Both dendritic cells and basophils have been shown to influence T helper 2 cell induction, however the relative importance of their roles remains unclear. Otsuka et al. find that basophils present hapten and peptide antigens to T cells, but are unable to present protein antigens in the absence of dendritic cells.
- Atsushi Otsuka
- , Saeko Nakajima
- & Kenji Kabashima