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| Open AccessBlood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
Factor XII initiates the intrinsic blood coagulation cascade and the kinin system. Here the authors show that Factor XII is elevated in the blood of multiple sclerosis patients, activates dendritic cells via CD87 and cAMP, and its blockade inhibits immunopathology in a mouse model of the disease.
- Kerstin Göbel
- , Susann Pankratz
- & Sven G. Meuth
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Article
| Open AccessThe PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages
Elevated IL-33 levels have been correlated with metastasis and poor prognosis. Here the authors show in mouse tumour xenograft models that PDGF-BB produced by tumour cells induces IL-33 via Sox7 in tumour pericytes, and IL-33 promotes metastasis through its effects on tumour-associated macrophages.
- Yunlong Yang
- , Patrik Andersson
- & Yihai Cao
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Article
| Open AccessEpidermal Notch1 recruits RORγ+ group 3 innate lymphoid cells to orchestrate normal skin repair
In normal skin, Notch directs keratinocytes to terminally differentiate. Here the authors show that Notch1 has a wider role in skin repair; Notch1 is activated in keratinocytes after damage and drives transcription of TNFα and inflammatory chemokines, which in turn recruit ILC3s and macrophages that promote repair.
- Zhi Li
- , Tom Hodgkinson
- & Carrie A. Ambler
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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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Article
| Open AccessClec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity
Clec4A4 is a C-type lectin receptor highly expressed by CD8α− dendritic cells. Here the authors show that its loss of function results in enhanced T cell responses and exacerbated autoimmunity, implicating Clec4A4 in limiting activation of the CD8α−dendritic cells.
- Tomofumi Uto
- , Tomohiro Fukaya
- & Katsuaki Sato
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Article
| Open AccessFNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice
FDNC4 is a poorly characterized homologue of FNDC5/irisin, a myokine induced by exercise. Here the authors show that FDNC4 increases macrophage survival in growth factor deprivation, inhibits phagocytosis and transcriptional responses to M1 and M2 polarizing stimuli, and protects mice from DSS-induced colitis.
- Madeleen Bosma
- , Marco Gerling
- & Pontus Almer Boström
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| Open AccessCalcium-sensing receptors signal constitutive macropinocytosis and facilitate the uptake of NOD2 ligands in macrophages
Macropinocytosis can be induced in several cell types by growth factors to promote nutrient acquisition. Here the authors find that constitutive macropinocytosis, unique to dendritic cells and macrophages, requires the activity of calcium-sensing receptors.
- Johnathan Canton
- , Daniel Schlam
- & Sergio Grinstein
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Article
| 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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Article
| Open AccessQuaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression
Post-transcriptional control of RNA is important in health and disease. Here, the authors show that the RNA-binding protein Quaking guides pre-mRNA splicing and transcript abundance during monocyte to macrophage differentiation, and that Quaking depletion impairs pro-atherogenic foam cell formation.
- Ruben G. de Bruin
- , Lily Shiue
- & Eric P. van der Veer
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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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Article
| Open AccessPerinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments
Cell migration through micrometric constraints is limited by low deformability of the nucleus. Here the authors show that in dendritic cells a perinuclear actin network nucleated by Arp2/3 increases nuclear deformation and allows the cells to pass through narrow constrictions, likely by rupturing the nuclear lamina.
- Hawa-Racine Thiam
- , Pablo Vargas
- & Matthieu Piel
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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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Article
| 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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| 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 AccessLocal T/B cooperation in inflamed tissues is supported by T follicular helper-like cells
In secondary lymphoid organs T follicular helper (Tfh) cells help B cells to develop into memory B and plasma cells. Here, the authors show that inflamed lung becomes a reservoir of activated B cells with a germinal centre phenotype, and T cells that exhibit Tfh-like properties despite not expressing classical Tfh markers.
- Dana Vu Van
- , Katja C. Beier
- & Andreas Hutloff
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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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| Open AccessF-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling
Endothelial cells can support leukocyte extravasation without causing vascular leakage, but the exact mechanism underlying this process has not been fully elucidated. Here the authors show that it is regulated through actomyosin-based endothelial pore confinement, which requires local endothelial RhoA activation.
- Niels Heemskerk
- , Lilian Schimmel
- & Jaap D. van Buul
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| Open AccessBone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells
Tissue-resident macrophages are mostly derived from embryonic progenitors. Scott et al. develop a mouse model to specifically deplete Kupffer cells (KC) in vivoand show that monocyte-derived cells can repopulate KC niche and behave similar to their embryonically-derived counterparts.
- Charlotte L. Scott
- , Fang Zheng
- & Martin Guilliams
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| Open AccessCX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production
Chemokine-driven infiltration of inflammatory macrophages is central to the muscle regenerative response to injury. Here the authors show that the function of infiltrating macrophages is also important as notexin-induced muscle injury in mice is rescued by CX3CR1 knockout owing to enhanced ApoE production.
- Ludovic Arnold
- , Hélène Perrin
- & Christophe Combadiere
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Article
| Open AccessTRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation
Transcriptional regulation of the interferon-β gene (Ifnb1) in macrophages is a critical immune event. Here, Ferri et al. show that, at late phases of macrophages activation, TRIM33 bound to a distal repressor element suppresses Ifnb1transcription by preventing recruitment of CBP/p300.
- Federica Ferri
- , Aude Parcelier
- & Paul-Henri Romeo
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| Open AccessHuman caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes
Human monocytes exhibit an unconventional one-step pathway of inflammasome activation and IL-1 release in response to LPS. Here the authors show that it is mediated by caspases 4 and 5, and characterize caspase 5 cleavage, Syk and calcium signalling as key mediators of this pathway.
- Elena Viganò
- , Catherine Emma Diamond
- & Alessandra Mortellaro
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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 AccessmiR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program
Fibroblast activity is regulated by tissue macrophages. Here the authors show that two miRNAs regulated by IL-4 and IL-13 in macrophages target SOCS1 and PPARγ and modulate profibrogenic macrophage program in vitro and in vivo, and that alterations of these miRNAs are found in fibrosis.
- Shicheng Su
- , Qiyi Zhao
- & Erwei Song
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NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures
NCR+type 3 innate lymphoid cells display lymphoid tissue-inducing ability. Here the authors show that these cells are increased in early-stage human lung cancer, respond to cancer cells and associated fibroblasts by producing cytokines and are associated to intratumoural ectopic lymphoid structures.
- Paolo Carrega
- , Fabrizio Loiacono
- & Guido Ferlazzo
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| Open AccessIntestinal macrophages arising from CCR2+ monocytes control pathogen infection by activating innate lymphoid cells
Monocytes are important for antimicrobial host defence in the intestine but the mechanism behind their protective function is not fully understood. Seo et al. show that intestinal macrophages derived from CCR2+ monocytes support clearance of pathogenic Citrobacter rodentiumthrough activation of group 3 innate lymphoid cells.
- Sang-Uk Seo
- , Peter Kuffa
- & Nobuhiko Kamada
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| Open AccessIL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells
The proinflammatory cytokine interleukin-1ß (IL-1ß) plays an important role in host defence against pathogens. Here the authors report a non-canonical pathway for IL-1 ß production in conventional dendritic cells that is induced by IL-21 via STAT3-dependent mechanism.
- Chi-Keung Wan
- , Peng Li
- & Warren J. Leonard
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Article |
Injectable cryogel-based whole-cell cancer vaccines
Immune responses are induced in the organized, cytokine-rich environment of lymph nodes, which can be mimicked by biomaterials. Here the authors show that injectable sponge-like gels decorated with immunostimulatory factors attract dendritic cells and boost antitumour immune responses in mice.
- Sidi A. Bencherif
- , R. Warren Sands
- & David J. Mooney
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| Open AccessIL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis
Pathological neovascularization causes blinding eye disease. Here the authors show that IL10 activates STAT3 signalling in the macrophages in the ageing eye, promoting their polarization towards a pro-angiogenic phenotype; interfering with this pathway reverses the pathology in a mouse model.
- Rei Nakamura
- , Abdoulaye Sene
- & Rajendra S. Apte
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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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| Open AccessIntestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes
Macrophages and dendritic cells residing in the lamina propria are involved in controlling mucosal immune balance. Here, the authors identify CD169+macrophages as contributors to the inflammation of DSS colitis through their role in mediating the recruitment of monocytes by secreting the cytokine CCL8.
- Kenichi Asano
- , Naomichi Takahashi
- & Masato Tanaka
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| Open AccessFunctional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst
Phagocytes employ multiple bactericidal mechanisms to kill microorganisms, including the generation of toxic superoxide and other reactive oxygen species. Here the authors utilize a multi-omics approach to identify and characterize new regulatory nodes implicated in mucosal immunity that control phagocyte oxidative burst.
- Daniel B. Graham
- , Christine E. Becker
- & Ramnik J. Xavier
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Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation
Syndecan-4 is a surface protein implicated in the regulation of cytoskeleton, adhesion and migration. Here the authors show that blocking syndecan-4 prevents dendritic cell migration into the lung and inhibits the development of allergic airway inflammation in mice.
- Tobias Polte
- , Susanne Petzold
- & Marco Averbeck
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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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| Open AccessCell migration and antigen capture are antagonistic processes coupled by myosin II in dendritic cells
Dendritic cells alternate between fast and slow migratory behaviours, however in the absence of a component of the antigen processing machinery, migration is uniform and fast. Chabaudet al. now show that slow migration results from the relocalisation of myosin II to the cell front where it promotes antigen capture.
- Mélanie Chabaud
- , Mélina L. Heuzé
- & Ana-Maria Lennon-Duménil
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Article
| Open AccessExosome-delivered microRNAs modulate the inflammatory response to endotoxin
Response to inflammatory stimuli such as endotoxin is coordinated at many levels. Here, the authors show that two microRNAs known to regulate inflammatory response inside the cell are secreted by dendritic cells and modulate inflammatory signalling in the neighbouring cells.
- Margaret Alexander
- , Ruozhen Hu
- & Ryan M. O’Connell
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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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Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages
Activation of innate immune responses is subject to versatile regulation. Here the authors show that a conserved LATS family kinase Stk38 limits proinflammatory signalling downstream of TLR9 in macrophages and protects mice from lethal sepsis by MEKK2 ubiquitination and degradation.
- Mingyue Wen
- , Xianwei Ma
- & Huazhang An
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Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis
Chronic pancreatitis is an inflammatory disease accompanied by fibrosis. Here the authors show that pancreatic stellate cells produce IL-4 and IL-13 that trigger alternative activation of macrophages, and that genetic or pharmacological inhibition of IL-4/IL-13 signaling ameliorates the disease.
- Jing Xue
- , Vishal Sharma
- & Aida Habtezion
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| 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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Article
| Open AccessCD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis
Dendritic cells are critical for initiation of immune responses and for induction of tolerance. Here the authors show that deletion of survival factor c-flip in CD11c-expressing cells subset perturbs CD8a+dendritic cell, NK and macrophage pools, and leads to development of autoimmune arthritis.
- Qi-Quan Huang
- , Harris Perlman
- & Richard M. Pope
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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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Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation
The inflammasomes are multiprotein structures that trigger inflammation in response to diverse stress conditions. Here, Ip and Medzhitov show that the NLRP3 and NLRC4 inflammasomes in macrophages act as sensors of hyperosmotic stress and participate in salt-induced inflammatory responses.
- W. K. Eddie Ip
- & Ruslan Medzhitov
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| Open AccessId1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation
Tumour progression is promoted by the generation of an immunosuppressive macroenvironment. Here, the authors demonstrate that the Inhibitor of Differentiation 1 promotes the switch from dendritic cell differentiation towards myeloid-derived suppressor cell expansion during tumour progression.
- Marianna Papaspyridonos
- , Irina Matei
- & David Lyden
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ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms
The life cycle of parasitic hookworms includes a developmental stage in the lungs, before reaching the gut where they mature into adults. Here Bouchery et al. show that Group 2 innate lymphoid cells (ILC2s) cooperate with CD4+T cells to inhibit the development of a model hookworm in the lungs of mice.
- Tiffany Bouchery
- , Ryan Kyle
- & Graham Le Gros
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Article
| Open AccessA dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells
How anti-helminth and allergic immune responses are initiated is poorly understood. Here the authors show that to trigger these responses, dendritic cells specifically require methyl-CpG-binding domain-2, a protein promoting repressed chromatin state.
- Peter C. Cook
- , Heather Owen
- & Andrew S. MacDonald
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| Open AccessCombinatorial code governing cellular responses to complex stimuli
Cells constantly integrate information from multiple stimuli. By considering every possible means by which two stimuli can interact, Cappuccio et al. define 10 interaction modes and demonstrate their preferential use by dendritic cells responding to different combinations of microbial and host inflammatory cues.
- Antonio Cappuccio
- , Raphaël Zollinger
- & Vassili Soumelis
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| Open AccessAPOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages
Aberrant RNA editing is linked to a range of neuropsychiatric and chronic diseases. Here Sharma et al. show that APOBEC3A can function as an RNA editing protein in response to physiological stimuli, significantly expanding our understanding of RNA editing and the role this may play in diseases.
- Shraddha Sharma
- , Santosh K. Patnaik
- & Bora E. Baysal