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| Open AccessMarginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling
Marginal zone B cells are mostly characterized in the context of host defense against bacterial blood-borne pathogens. Here the authors show that TLR4 signaling in these cells requires Fcα/μR (CD351) and that they are a major source of IL-6 in a mouse model of sepsis.
- Shin-ichiro Honda
- , Kazuki Sato
- & Akira Shibuya
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| Open AccessThe obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation
Visceral and subcutaneous fat are associated with different metabolic risk, but mediators of such depot specific effects are not very well known. Here the authors identify the transcriptional regulator, TRIP-Br2, as a regulator of endoplasmic reticulum (ER) stress-induced inflammatory responses specifically in visceral fat.
- Guifen Qiang
- , Hyerim Whang Kong
- & Chong Wee Liew
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Article
| Open AccessMincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution
Resolution of granulomas in mycobacterial infection requires macrophages to switch from cytokine to nitric oxide (NO) production. Here the authors show that Mincle stimulates translation of the key NO synthesis genes by a mechanism dependent on p38-mediated hypusination of eiF5A.
- Wook-Bin Lee
- , Ji-Seon Kang
- & Young-Joon Kim
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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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Article
| Open AccessAirway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
The mechanisms driving lung inflammation and remodelling in chronic obstructive pulmonary disease (COPD) are incompletely understood. Here the authors show that lack of secretory IgA promotes bacterial invasion in small airways, resulting in leukocyte recruitment and a COPD-like phenotype.
- Bradley W. Richmond
- , Robert M. Brucker
- & Vasiliy V. Polosukhin
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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 AccessIL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis
IL-1-mediated inflammation contributes to the pathogenesis of cystic fibrosis. Here the authors show that this is largely due to NLRP3 activation, whereas NLRP4 induces IL-1Ra, limiting the overall inflammasome activity and providing a therapeutic angle to ameliorate the disease.
- Rossana G. Iannitti
- , Valerio Napolioni
- & Luigina Romani
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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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Article
| 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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Article
| Open AccessOpposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality
Scorpion venom causes thousands of deaths worldwide. Here the authors show that the envenomation acts via prostaglandin E2 leading to inflammasome activation and lung pathology, counterbalanced by inflammation-limiting LTB4, and that COX inhibitors or exogenous LTB4 rescue the venom-induced mortality in mice.
- Karina F. Zoccal
- , Carlos A. Sorgi
- & Lúcia H. Faccioli
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Article
| Open AccessThe REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis
REGγ is a component of ubiquitin-independent 20S proteasome that targets many regulatory proteins for degradation. Here the authors show that REGγ is induced in DSS colitis and promotes degradation of IκBɛ, and that REGγ-deficient mice have less NFκB activation and are more resistant to the disease.
- Jinjin Xu
- , Lei Zhou
- & Xiaotao Li
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Article
| 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 AccessNLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions
NK cell tolerance to self-MHCI levels is calibrated during their development. Here the authors show that this tolerance is overcome by an inflammatory environment and that NLRC5 protects T cells from NK cell-mediated elimination by maintaining high MHCI expression.
- Kristina Ludigs
- , Camilla Jandus
- & Greta Guarda
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| Open AccessEndothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4
The RNAse III endonuclease Dicer is crucial for processing of pre-miRNAs in health and disease. Here the authors show that endothelial Dicer promotes atherosclerosis by increasing miR-103 levels leading to suppression of the anti-inflammatory transcription factor KLF4, thus suggesting a novel approach to treat this disease.
- Petra Hartmann
- , Zhe Zhou
- & Andreas Schober
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Article
| Open AccessPKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications
Protein kinase R (PKR) has been suggested to act as a mediator of ER stress and inflammation in obesity. Here, Lancaster et al. find that genetic loss of PKR does not alter the development of obesity, and suggest that the use of littermate controls may explain differences in mouse knockout phenotypes.
- G. I. Lancaster
- , H. L. Kammoun
- & M. A. Febbraio
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| Open AccessEndomucin prevents leukocyte–endothelial cell adhesion and has a critical role under resting and inflammatory conditions
Endomucin is expressed by endothelial cells that line postcapillary venules—the site of leukocyte recruitment during inflammation. Zahr et al.show that endomucin is an anti-adhesive molecule that is downregulated by the cytokine TNF-a and thereby helps in the transition from a quiescent to a pro-adhesive inflamed endothelium.
- Alisar Zahr
- , Pilar Alcaide
- & Pablo Argüeso
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| Open AccessCytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis
Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al. show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.
- Shrikant R. Mulay
- , Jyaysi Desai
- & Hans-Joachim Anders
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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 AccessPre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination
Ageing is associated with poor responses to vaccines but the underlying mechanism remains unclear. Here the authors use a systems-based approach to define molecular signatures present before vaccination that correlate with non-responsiveness to hepatitis B vaccination in healthy, elderly adults.
- Slim Fourati
- , Razvan Cristescu
- & Rafick-Pierre Sékaly
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| Open AccessLarge-scale inference of protein tissue origin in gram-positive sepsis plasma using quantitative targeted proteomics
Sepsis can lead to multiple organ failure that could potentially be reflected by change in plasma protein abundance. Here the authors describe a proteomics strategy that allows the determination of plasma proteins tissue origin in a quantitative manner for use as biomarkers—illustrated in a mouse model of sepsis.
- Erik Malmström
- , Ola Kilsgård
- & Johan Malmström
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Article
| Open AccessEndothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
Atherosclerosis is an inflammatory disease with limited therapeutic options. Here, the authors show that protein kinase MAP4K4 regulates vascular inflammation underlying atherosclerotic plaque development and that its inhibition prevents the disease and promotes lesion regression in mice, proposing a new atherosclerosis treatment.
- Rachel J. Roth Flach
- , Athanasia Skoura
- & Michael P. Czech
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| Open AccessInhibition of inflammasome activation by Coxiella burnetii type IV secretion system effector IcaA
Coxiella burnetti primarily infects alveolar macrophages and causes an acute form of pneumonia called Q fever. Cunha et al. describe a type IV secretion effector, termed IcaA, expressed by Coxiella burnetiithat inhibits inflammasome activation and therefore may contribute to innate immune evasion by bacteria.
- Larissa D. Cunha
- , Juliana M. Ribeiro
- & Dario S. Zamboni
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| Open AccessSepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy
Sepsis patients often develop muscle atrophy that can last for years. Here the authors show in a mouse model that sepsis causes long-term impairment of the satellite cells, affecting mitochondrial function and energy metabolism, and that injection of mesenchymal stem cells restores satellite cell metabolism and muscle regeneration.
- P. Rocheteau
- , L. Chatre
- & F. Chrétien
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The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a severe pulmonary complication seen in preterm infants, the molecular mechanisms of which are not clear. Here the authors establish a link between NLRP3 inflammasome activation, leading to production of pro-inflammatory cytokine IL1β, and the development of BPD.
- Jie Liao
- , Vishal S. Kapadia
- & Rashmin C. Savani
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| Open AccessCCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells
Little is known regarding migration of Th17 cells that produce distinct cytokines implicated in protection and pathology. Kara et al. show that a switch from CCR6 to CCR2 by Th17 cells defines a signature (CCR6−CCR2+) of GM-CSF+Th17 cells and drives pathology in a mouse model of autoimmunity.
- Ervin E. Kara
- , Duncan R. McKenzie
- & Shaun R. McColl
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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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Article
| Open AccessNdrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2
T cell clonal anergy is mediated by Egr2 but its downstream effectors have not been characterized. Here the authors show that Egr2 activates Ndrg1, which is critical for the anergy state, while anergy-counteracting signals IL-2 or CD-28 promote Ndrg1 phosphorylation and degradation.
- Yu Mi Oh
- , Hyung Bae Park
- & Kyungho Choi
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Article
| Open AccessThe matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis
Stiffness in the extracellular matrix is thought to contribute to pathological cutaneous fibrosis. Here, the authors identify the elastic fibre protein Fibulin-5 as a link and potential therapeutic target mediating the transition of cutaneous stiffening to fibrosis.
- Manando Nakasaki
- , Yongsung Hwang
- & Colin Jamora
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| Open AccessAntigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1
Antigen stimulation in vivocan reprogram T regulatory cells to lose the expression of Foxp3 and become effector cells. Here the authors show that the mechanism involves dephosphorylation of STAT5 by PTPN2 and downregulation of Foxo1 by miR-182.
- Evita Bothur
- , Hartmann Raifer
- & Michael Lohoff
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Article
| 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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| Open Access‘Emergency exit’ of bone-marrow-resident CD34+DNAM-1brightCXCR4+-committed lymphoid precursors during chronic infection and inflammation
Lymphocytes are on high demand during chronic infections. Here, the authors show that human lymphoid precursors, normally found in the bone marrow, circulate in the blood of chronic inflammation patients and give rise to natural killer cells and other lymphocytes.
- Federica Bozzano
- , Francesco Marras
- & Andrea De Maria
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| Open AccessEomesodermin-expressing T-helper cells are essential for chronic neuroinflammation
Eomesodermin is a master regulator of effector CD8+ T cells. Here the authors show that it also plays a critical role in pathogenic CD4+ cells in a mouse model of multiple sclerosis, and its inactivation ameliorates the chronic stage of the disease.
- Ben J. E. Raveney
- , Shinji Oki
- & Takashi Yamamura
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| Open AccessMatrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection
Proteases degrade extracellular matrix during inflammation, releasing peptides that can recruit neutrophils. Here the authors show that degradation of such bioactive peptide by the enzyme leukotriene A4 hydrolase is critical to limit pulmonary inflammation during bacterial infection in mice.
- Samia Akthar
- , Dhiren F. Patel
- & Robert J. Snelgrove
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| Open AccessHIV–tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling
Some patients with HIV-associated tuberculosis develop an immune reconstitution inflammatory syndrome (TB-IRIS) in response to antiretroviral therapy. Here the authors identify genes differentially expressed in patients likely to progress to TB-IRIS and find activation of Toll-like receptor and inflammasome pathways.
- Rachel P. J. Lai
- , Graeme Meintjes
- & Robert J. Wilkinson
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Article
| Open AccessSialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice
Intestinal inflammation is often associated with a shift in microbiota composition but the mechanisms are unclear. Here the authors show that an increase in caecal sialidase activity occurring during intestinal inflammation promotes the expansion of Enterobacteriaceae, which can lead to exacerbated inflammatory response.
- Yen-Lin Huang
- , Christophe Chassard
- & Thierry Hennet
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| Open AccessExperimental colitis in SIV-uninfected rhesus macaques recapitulates important features of pathogenic SIV infection
HIV-1 infection in humans and SIV infection in rhesus macaques are associated with mucosal damage to the gastrointestinal tract, microbial translocation and chronic immune activation. Here the authors develop a non-human primate DSS colitis model that recapitulates these aspects of the disease in uninfected rhesus macaques.
- Xing Pei Hao
- , Carissa M. Lucero
- & Jacob D. Estes
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Article |
Oestrogen sulfotransferase ablation sensitizes mice to sepsis
Sepsis, a systemic inflammatory response to bacterial infection, can lead to organ failure and death. Here, Chai et al.investigate the mechanisms behind the septic response and identify the role of oestrogen sulfotransferase in this process in mice.
- Xiaojuan Chai
- , Yan Guo
- & Wen Xie
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Article
| Open AccessPannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation
Endothelial cell activation by inflammation requires extracellular ATP release. Here the authors show that TNF-α induces Src-family kinase-dependent ATP release by Pannexin1 channels in endothelial cells, and that Pannexin1 is required for leukocyte adhesion and emigration into the inflamed tissue.
- Alexander W. Lohman
- , Igor L. Leskov
- & Brant E. Isakson
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Article
| Open AccessAssembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC
The AIM2 inflammasome complex is essential for defence against a number of human pathogens but how it assembles upon recognition of foreign DNA remains incompletely understood. Here Morrone et al.suggest the AIM2 pyrin domain acts in both DNA binding and filament assembly to generate a structural template for complex assembly.
- Seamus R. Morrone
- , Mariusz Matyszewski
- & Jungsan Sohn
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Article
| 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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PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis
Platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs) promotes atherogenesis. Here, the authors show that mutant mice with increased PDGF activity in VSMCs have augmented STAT1-dependent chemokine signals resulting in artery wall inflammation and formation of advanced plaque morphologies clinically relevant in humans.
- Chaoyong He
- , Shayna C. Medley
- & Lorin E. Olson
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Article
| Open AccessGlucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1
Endothelial damage is a major component of acute lung injury pathogenesis. Here the authors show that in a mouse model of acute lung injury, glucocorticoids induce sphingosine kinase 1 production in macrophages, promoting endothelial barrier function and ameliorating the disease.
- Sabine Vettorazzi
- , Constantin Bode
- & Jan P. Tuckermann
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Article
| Open AccessCaspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3
Inflammasome activation requires a complex and incompletely understood network of signalling events. Here the authors characterize step-by-step contributions of TLR3, caspase-8, RIPK3 and MLKL to the activation of NLRP3 inflammasome in response to double-stranded RNA.
- Seokwon Kang
- , Teresa Fernandes-Alnemri
- & Emad S. Alnemri
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Article
| Open AccessThe immunomodulating V and W proteins of Nipah virus determine disease course
Nipah virus (NiV) can be transmitted from bats and other animals to humans, causing severe encephalitis and respiratory disease. Here, Satterfield et al.show that the W protein of NiV modulates the host immune response and determines disease course in a ferret model of infection.
- Benjamin A. Satterfield
- , Robert W. Cross
- & Chad E. Mire
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Article
| Open AccessBruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury
Activation of inflammasome contributes to several pathologies. Here, the authors show that Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation, and that blocking it with the FDA-approved inhibitor ibrutinib limits tissue damage in a mouse model of ischaemic stroke.
- Minako Ito
- , Takashi Shichita
- & Rimpei Morita
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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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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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Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma
Aortic dissection and intramural haematoma are caused by separation of the aortic wall via an unknown mechanism. Here the authors show that the inflammatory cytokine, granulocyte macrophage colony-stimulating factor, is a central regulatory molecule causative of these conditions in mice and humans.
- Bo-Kyung Son
- , Daigo Sawaki
- & Toru Suzuki