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Article
| Open AccessExpression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease
IgG4-related disease is a fibro-inflammatory disorder, characterized by infiltration of IgG4 producing plasma cells in the target organs. Here authors show that the affected B cells express less ubiquitin-specific protease 25 (USP25), and this results in activation of multiple pathways involved in cytoskeleton reorganization, inflammation and energy metabolism, which might govern disease pathogenesis.
- Panpan Jiang
- , Yukai Jing
- & Chaohong Liu
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Article
| Open AccessSingle-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessEtrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells
The clinical success of anti- αEβ7 antibody Etrolizumab for Crohn’s disease is less than what is expected based on proof-of-concept studies. Here authors show, by characterization of T cells from Etrolizumab-treated patients, in vitro functional assays and reanalysis of public single cell datasets on Etrolizumab-treated patients, that at high level of T cell activation, which characterises T cells in Crohn’s disease, E-Cadherin-αEβ7 interactions become resistant to Etrolizumab inhibition.
- Maximilian Wiendl
- , Mark Dedden
- & Sebastian Zundler
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Article
| Open AccessWNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease
Fibroblast heterogeneity is a recognized feature in chronic kidney disease, and although fibrosis is integrant to the pathology, it is lesser known which of the fibroblast populations contribute. Here authors describe a population of proinflammatory fibroblasts, which are found in close proximity to macrophages and may facilitate their recruitment and acquisition of a FOLR2+, pathogenic phenotype.
- Camille Cohen
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessGasdermin E dictates inflammatory responses by controlling the mode of neutrophil death
Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.
- Fengxia Ma
- , Laxman Ghimire
- & Hongbo R. Luo
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Article
| Open AccessThe transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure
Acute hypoxemic respiratory failure (AHRF) and the associated lung immune cell features are not well understood. Here the authors use CITE-Seq to analyse the transcriptomic and phenotypic profile of lung and blood cells from a longitudinal cohort of patients with AHRF to identify gene signatures and cell surface proteins associated with disease severity.
- Eric D. Morrell
- , Sarah E. Holton
- & Carmen Mikacenic
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Article
| Open AccessTLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.
- Gang Liu
- , Tatt Jhong Haw
- & Philip M. Hansbro
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessSingle-atom catalysts-based catalytic ROS clearance for efficient psoriasis treatment and relapse prevention via restoring ESR1
Psoriasis is a common inflammatory disease, and the overproduction of reactive oxygen species (ROS) in skin lesions plays a critical role in the progress of psoriasis. Here, the authors report the use of multienzyme-inspired biomimetic iron single-atom catalysts (FeN4O2-SACs) with broad-spectrum ROS-scavenging capability for psoriasis treatment and relapse prevention via related gene restoration.
- Xiangyu Lu
- , Le Kuai
- & Jianlin Shi
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Article
| Open AccessMultifaceted analysis of cross-tissue transcriptomes reveals phenotype–endotype associations in atopic dermatitis
Atopic dermatitis is an inflammatory skin disease featuring systemic involvement. Here authors show that the two major clinical manifestations of the disease, erythema and papulation, are distinguished by differential interplay between local skin and systemic immunity, uncovered by integrated transcriptomics.
- Aiko Sekita
- , Hiroshi Kawasaki
- & Haruhiko Koseki
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Article
| Open AccessOrai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
The regulation and intracellular transport of Ca2+ in immune cells involves Ca2+ release-activated Ca2+ (CRAC) channels. Here the authors show targeting CRAC components Orai1 and Orai2 modulates pulmonary ILC2 cells altering their metabolism, function and is linked to alleviation of immunopathology in a murine model of allergic airway disease.
- Emily Howard
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessCREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
The mechanistic functions of neutrophils in skin inflammation are not fully understood. Here the authors use human psoriasis samples and a mouse model of skin inflammation to study neutrophils and find a CXCR4hi population of NET-forming, phagocytic neutrophils whose induction depends on the transcription factor CREB1.
- Jiaoling Chen
- , Yaxing Bai
- & Shuai Shao
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Article
| Open AccessSolar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary–lung axis
Allergic asthma is episodic and associated with seasonal changes which may have links with UV exposure levels. Here the authors propose a link between UVB exposure and ILC2 function through α-MSH released from the pituitary gland which accumulates in the serum and alters ILC2 function through the MC5R receptor.
- Yuying Huang
- , Lin Zhu
- & Bing Sun
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Article
| Open AccessType-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
The most appreciated producers of pathogenic type-2 cytokines in asthma are T helper 2 cells and group 2 innate lymphoid cells, however, CD8+ cytotoxic T cells are also capable of secreting these mediators. Authors here show that IL-33, a cytokine that is produced by the inflammatory microenvironment, promotes type-2 cytotoxic T cell development, which is linked to asthma exacerbations.
- Esmee K. van der Ploeg
- , Lisette Krabbendam
- & Ralph Stadhouders
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Article
| Open AccessIL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation
Interleukin 9 (IL-9) is a cytokine that plays causative role in airway inflammation of both infectious and allergic origin. Here authors show in a mouse model of SARS-CoV-2 infection that IL-9, predominantly produced by helper T cells, plays a critical pathogenic role in COVID-19 via an inflammatory pathway involving the transcription factor Foxo1.
- Srikanth Sadhu
- , Rajdeep Dalal
- & Amit Awasthi
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Article
| Open AccessSUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
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Article
| Open AccessInherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling
Mutations that impact the function of the Arp2/3 complex are known to cause inborn errors of immunity. Here the authors describe biallelic null mutations in the ARPC5 subunit of Arp2/3 that disrupt actin function and cytokine signaling, causing infections, autoimmunity, inflammation and dysmorphisms.
- Cristiane J. Nunes-Santos
- , HyeSun Kuehn
- & Sergio D. Rosenzweig
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Article
| Open AccessStructural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84
The orphan GPR84 plays important roles in inflammation, fibrosis, and metabolism. Here, authors report cryo-EM structures of the receptor bound to two ligands, with insights into ligand binding and entry from the extracellular milieu.
- Heng Liu
- , Qing Zhang
- & Wanchao Yin
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Article
| Open AccessImpaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis
Inflammatory skin diseases are frequently associated with dysregulation of cutaneous immunity. Here the authors perform human challenge with house dust mite allergen in patients with atopic dermatitis and explore the molecular network determining tolerance versus inflammation and identify a role for metallothioneins in the modulation of allergen induced inflammation.
- Sofia Sirvent
- , Andres F. Vallejo
- & Marta E. Polak
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Article
| Open AccessLung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.
- Youn Jung Choi
- , Ji-Seung Yoo
- & Jae U. Jung
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Article
| Open AccessConstitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.
- Adriana A. de Jesus
- , Guibin Chen
- & Raphaela Goldbach-Mansky
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Article
| Open AccessSpatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases
Inflammatory skin diseases involve various different immune cells in a localised area. Here the authors use spatial transcriptomics to show that disease relevant cytokine transcripts are sparsely expressed in lesional skin, yet are associated with local amplification cascades that promote skin inflammation.
- A. Schäbitz
- , C. Hillig
- & S. Eyerich
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Article
| Open AccessCD1a promotes systemic manifestations of skin inflammation
Skin inflammation is often accompanied by systemic disease, yet the pathways that regulate this escalation are little known. Here authors show that transgenic expression of human CD1a in mice leads to the escalation of experimental skin inflammation and systemic inflammatory disease, and the generalized symptoms could be alleviated by blocking antibodies developed against CD1a.
- Clare S. Hardman
- , Yi-Ling Chen
- & Graham S. Ogg
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Article
| Open AccessLow-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes
Low-dose interleukin-2 is showing promise in the treatment of several autoimmune inflammatory diseases. Here authors map the trajectory of cellular and transcriptional changes in type 1 diabetes patients receiving an interval dosing interleukin-2 regimen, which shows an anti-inflammatory gene expression signature shared by all immune cell types analysed, persisting for at least a month after ending treatment.
- Jia-Yuan Zhang
- , Fiona Hamey
- & Ricardo C. Ferreira
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Article
| Open AccessHigh-throughput screening of caterpillars as a platform to study host–microbe interactions and enteric immunity
Here, combining diagnostic imaging modalities and in vivo assays, Windfelder and colleagues established tobacco hornworm larvae Manduca sexta as an alternative high-throughput platform to study the innate immunity of the gut and host-pathogen interactions. Using the platform, the authors identify mediators of gut inflammation, differentiate pathogens from gut mutualist bacteria, and demonstrate pharmacological interventions.
- Anton G. Windfelder
- , Frank H. H. Müller
- & Ulrich Flögel
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Article
| Open AccessThe Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis
This study reports reduced expression of the chromatin and splicing regulator HP1γ in inflammatory bowel disease (IBD) and shows that HP1γ protects against pervasive RNA splicing leading to toxic mRNA products detected in IBD, like progerin.
- Jorge Mata-Garrido
- , Yao Xiang
- & Laurence Arbibe
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Article
| Open AccessFerritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis
Hyperferritinemic syndrome is a collective term for a group of severe inflammatory conditions distinguished by high ferritin levels, including adult-onset Still’s disease and COVID-19. Here authors show in an animal model that high ferritin levels are not just a sign of hyperinflammation but also a pathogenic factor that triggers neutrophil leukocyte activation and extracellular trap formation.
- Jinchao Jia
- , Mengyan Wang
- & Qiongyi Hu
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Article
| Open AccessEpithelial coxsackievirus adenovirus receptor promotes house dust mite-induced lung inflammation
The epithelial protein Coxsackievirus Adenovirus Receptor (CAR) is a virus receptor but may have other functions. Here the authors show that deletion of CAR in mice leads to reduced house dust mite-induced lung inflammation, reduced neutrophil accumulation and alterations in airway remodelling.
- Elena Ortiz-Zapater
- , Dustin C. Bagley
- & Maddy Parsons
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Article
| Open AccessDNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
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Article
| Open AccessPD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability
Regulatory T (Treg) cells have been implicated in the induction of airway tolerance and amelioration of respiratory duct inflammation. Here the authors show, using PD-L2 deficient mice, that the immune suppression signal from PD-L2 is important for modulating Treg cell metabolism and function for proper induction of respiratory tolerance in mice.
- Benjamin P. Hurrell
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessCigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells
Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
- Jongho Ham
- , Jihyun Kim
- & Hye Young Kim
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Article
| Open AccessHigh-dimensional profiling reveals Tc17 cell enrichment in active Crohn’s disease and identifies a potentially targetable signature
The T cell compartment in patients with Crohn's disease is dysregulated. Here the authors use cytometric profiling to reveal an enrichment of distinct Tc17 cells during active Crohn's disease and may suggest CD6 as a potential target for therapeutic studies.
- A.-M. Globig
- , A. V. Hipp
- & B. Bengsch
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Article
| Open AccessDeficiency in coatomer complex I causes aberrant activation of STING signalling
Mutations in the coatomer complex I can result in endoplasmic reticulum stress and inflammatory consequences. Here authors define aberrant activation of the STING immunosensing pathway in a disturbed coatmer complex context and the therapeutic modulation of this axis to counter the associated immunopathology.
- Annemarie Steiner
- , Katja Hrovat-Schaale
- & Seth L. Masters
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Article
| Open AccessConstruction of a two-dimensional artificial antioxidase for nanocatalytic rheumatoid arthritis treatment
Inflammatory diseases such as rheumatoid arthritis are associated with high reactive oxygen species levels. Here, the authors report on 2D metal-organic frameworks as an artificial antioxidase with the same manganese coordination centre as two natural enzymes, and demonstrate their anti-inflammatory effects and anti-arthritic effects in vivo.
- Bowen Yang
- , Heliang Yao
- & Jianlin Shi
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Article
| Open AccessHomeostatic serum IgE is secreted by plasma cells in the thymus and enhances mast cell survival
Elevated levels of IgE is associated with a range of allergic pathology but the source of such IgE producing B cells during the steady state is poorly understood. Here, Kwon et al. show that homeostatic IgE is secreted by plasma cells in the thymus and link this to mast cell survival.
- Dong-il Kwon
- , Eun Seo Park
- & You Jeong Lee
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Article
| Open AccessProtective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection
Infection with SARS-COV-2 can result in self-limited upper airway infection or progress to a more systemic inflammatory condition including pneumonic COVID-19. Here the authors utilise a multi-omics approach to interrogate the immune response of patients with self-limiting upper respiratory SARS-CoV-2 infection and reveal a temporal immune trajectory they associate with viral containment and restriction from pneumonic progressive disease.
- Kami Pekayvaz
- , Alexander Leunig
- & Leo Nicolai
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Article
| Open AccessTolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia
Anti-drug antibodies (ADA) induced by biologic drugs may hamper the efficacy of treatment, so inhibiting ADA induction is desirable. Here, in two clinical trials, the authors show that ImmTOR, previously reported to reduce drug immunogenicity in animal studies, helps mitigate ADA induced by pegylated uricase for treating patients with hyperuricemia.
- Earl Sands
- , Alan Kivitz
- & Takashi Kei Kishimoto
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Article
| Open AccessOxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Oxylipins are lipid mediators generated during infection for regulating inflammatory responses, but how they are removed is not completely clear. Here the authors show that cellular oxylipin removal is linked to mitochondria β-oxidation by CPT1, a mitochondria lipid importer protein, to serve as a metabolic checkpoint for oxylipin homeostasis and inflammation.
- Mariya Misheva
- , Konstantinos Kotzamanis
- & Valerie B. O’Donnell
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Article
| Open AccessRare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.
- Sarah Grosche
- , Ingo Marenholz
- & Young-Ae Lee
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Article
| Open AccessSingle-cell RNA sequencing of peripheral blood mononuclear cells from acute Kawasaki disease patients
Immune cell changes are associated with Kawasaki disease (KD) pathogenesis. Here, using single cell RNA sequencing of PBMC, the authors show monocyte inflammatory genes are over-expressed in KD and TCR and BCR clonotype sequences show oligoclonal expansions after intravenous immunoglobulin therapy.
- Zhen Wang
- , Lijian Xie
- & Min Huang
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Article
| Open AccessConserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation
T regulatory (Treg) cells can differentiate into effector Treg (eTreg) cells that might be functional in inflammatory diseases. Using RNA sequencing and epigenetic profiling, the authors show that eTreg signatures in juvenile idiopathic arthritis joints are similar to tumour microenvironment (TME) Treg cells and are affected by tissue-specific epigenetic regulation.
- Gerdien Mijnheer
- , Lisanne Lutter
- & Femke van Wijk
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Article
| Open AccessDual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice
Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.
- Eva Conde
- , Romain Bertrand
- & Laurent L. Reber
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Article
| Open AccessPancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation
Glycoprotein-2 (GP-2) can protect the intestinal epithelial barrier from bacteria and is associated with protection against Crohn’s disease. Here, the authors show pancreatic GP-2 is the source of the intestine’s luminal GP-2 that binds bacteria and prevents them from attaching to the epithelium, also limiting pathology in a DSS colitis mouse model.
- Yosuke Kurashima
- , Takaaki Kigoshi
- & Hiroshi Kiyono
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Article
| Open AccessUbiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
RIPK1 is a critical kinase which mediates necroptosis, apoptosis and inflammation. Regulation of RIPK1 by ubiquitination is being intensively investigated. Here, the authors made knock-in RIPK1-K612R mice and demonstrate that this mutation alters the RIPK1 ubiquitinylation pattern and inhibits its prodeath kinase activity in response to TNFα but sensitizes cell death to TLRs signals.
- Xingyan Li
- , Mengmeng Zhang
- & Junying Yuan
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Article
| Open AccessDisease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a progressing disease, with lung but not gut microbiota implicated in its etiology. Here the authors compare the stool from patients with COPD and healthy controls to find specific gut bacteria and metabolites associated with active disease, thereby hinting at a potential role for the gut microbiome in COPD.
- Kate L. Bowerman
- , Saima Firdous Rehman
- & Philip M. Hansbro
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Matters Arising
| Open AccessReply to “Acid inhibitors and allergy: comorbidity, causation and confusion”
- Erika Jensen-Jarolim
- , Michael Kundi
- & Galateja Jordakieva
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Article
| Open AccessA missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
- Joanne M. Hildebrand
- , Maria Kauppi
- & John Silke
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Article
| Open AccessMD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy
The mechanisms underlying cardiac inflammation in diabetic cardiomyopathy are incompletely understood. Here the authors show that advanced glycation end products bind to the TLR4 co-receptor MD2 initiating pro-inflammatory pathways.
- Yi Wang
- , Wu Luo
- & Guang Liang