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| Open AccessFecal microbiota transplantation in HIV: A pilot placebo-controlled study
It is unknown whether capsulized fecal microbiota transplantation (FMT) can modify the microbiota of people with HIV. Here, the authors report the results of a pilot double-blind study, where 30 HIV-infected subjects on ART were randomized to either weekly oral FMT capsules or placebo for 8 weeks, and show that transplanted microbiota successfully engrafts and is able to attenuate HIV-associated dysbiosis.
- Sergio Serrano-Villar
- , Alba Talavera-Rodríguez
- & Santiago Moreno
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Article
| Open AccessNOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn’s disease
Trafficking of IgA/commensal complex in the gut has been implicated in inflammatory bowel diseases such as Crohn’s disease, but molecular insights are still lacking. Here the authors show, using mouse model or human cells, that NOD2 mutation increases IgA transport, potentially by altering gut microfold cells from the gut, to impact gut inflammation.
- Nicolas Rochereau
- , Xavier Roblin
- & Stéphane Paul
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| 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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Article
| Open AccessRepurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
Inflammasome activation may contribute to type 2 diabetes, but whether targeting inflammasome is beneficial is unclear. Here the authors show that repurposing nucleoside reverse transcriptase inhibitors for inhibiting inflammasome activation is associated with reduced diabetes development in people and improves insulin sensitivity in experimental settings.
- Jayakrishna Ambati
- , Joseph Magagnoli
- & Bradley D. Gelfand
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| Open AccessSingle-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis
Psoriatic arthritis (PsA) commonly affects patients with skin psoriasis, but its pathogenesis is still unclear. Here the authors use two types of single-cells data, mass cytometry and RNA sequencing, to describe the expansion and diversity of synovial, but not peripheral blood, CD8 T cells from PsA patients to provide a molecular immune landscape for PsA.
- Frank Penkava
- , Martin Del Castillo Velasco-Herrera
- & M. Hussein Al-Mossawi
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Article
| Open AccessDR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus
Group 2 innate lymphoid cells (ILC2s) are immune cells present in adipose tissue that contribute to metabolic homeostasis. Here the authors show that Death Receptor 3 (DR3) engagement on ILC2s ameliorates glucose tolerance, protects against insulin-resistance onset and reverses established insulin-resistance.
- Pedram Shafiei-Jahani
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessMucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity
Inflammation, immune cells and the host microbiota are intimately linked in the pathophysiology of obesity and diabetes. Here the authors show mucosal-associated invariant T cells fuel inflammation in the tissues and serve a function in promoting metabolic breakdown, polarising macrophage populations and inducing dysbiosis of the intestinal microbiota.
- Amine Toubal
- , Badr Kiaf
- & Agnès Lehuen
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Article
| Open AccessInflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis
STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.
- Yun Liao
- , Junjie Zhao
- & Xiaoxia Li
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Article
| Open AccessIncreased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling
Here Kumar et al. show that increased intestinal permeability reduces hepatic de novo lipogenesis, affecting plasma membrane fluidity and lifespan of RBCs, and the resulting increase in iron levels promotes bacterial growth. This mechanism may explain the increased risk of sepsis associated with inflammatory bowel disease.
- Manish Kumar
- , Aralia Leon Coria
- & Kris Chadee
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Article
| Open AccessGM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis
Spondyloarthritis pathology is manifested by increased myeloid infiltration of the joints. Here the authors show that in a mouse model of spondyloarthritis, a single dose of a microbial ligand curdlan induces persistent extramedullary myelopoiesis in the spleen and joints, which is driven by GM-CSF and can be amplified by exogenous IL-33.
- Daniel Regan-Komito
- , James W. Swann
- & Thibault Griseri
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Article
| 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 AccessTFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths
TFF3 secretion by goblet cells regulates mucus viscosity and wound healing, but a receptor for TFF3 has not been identified. Here, the authors show that TFF3 binds LINGO2 to de-repress and enhance EGFR signaling that drives wound healing and immunity against helminths.
- Nicole Maloney Belle
- , Yingbiao Ji
- & De’Broski R. Herbert
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Article
| Open AccessGalectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease
The authors show that Galectin-3 is up–regulated in brain tissues from patients and a mouse model of Huntington’s disease (HD) and correlates with disease severity. Galectin-3 accumulates at damaged lysosomes in HD microglia, prevents the clearance of damaged lysosomes, and promotes inflammation.
- Jian Jing Siew
- , Hui-Mei Chen
- & Yijuang Chern
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Article
| Open AccessMass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases
Distinguishing clinical subtypes of IBD is critical for optimal treatments, outcome prediction, and better understanding of disease pathogenesis. Here the authors phenotype blood and intestinal immune cells by mass cytometry and identify signatures associated with distinct disease states.
- Samuel J. S. Rubin
- , Lawrence Bai
- & Aida Habtezion
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Article
| Open AccessPhysical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis
Maintaining the intestinal barrier function requires a balance of multiple signalling pathways. Here the authors show that A20, an anti-inflammatory and anti-apoptotic protein, and Atg1611, an autophagy regulator, cross-regulate their respective protein levels and function to serve compensatory and redundant roles in fine-tuning gut barrier homeostasis.
- Karolina Slowicka
- , Inmaculada Serramito-Gómez
- & Geert van Loo
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Article
| Open AccessMajor vault protein suppresses obesity and atherosclerosis through inhibiting IKK–NF-κB signaling mediated inflammation
Metabolic diseases are associated with chronic, low-grade inflammation. Here the authors show that major vault protein (MVP) suppresses NF-κB signalling in macrophages via an IRAK1–TRAF6 axis and that loss of MVP in myeloid cells exacerbates the inflammatory response in mice fed a high fat diet.
- Jingjing Ben
- , Bin Jiang
- & Qi Chen
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Article
| Open AccessA late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation
Allograft can induces local chronic inflammation, but how this feeds back to regulating late immunity is still not clear. Here the authors show, by charactering B cell transcriptome landscape dynamic in human allografts and in mouse kidneys transitioning from acute to chronic injury, that late B cell activation is associated with renal dysfunction and inflammation.
- Pietro E. Cippà
- , Jing Liu
- & Andrew P. McMahon
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| Open AccessCostimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes
Type-2 innate lymphoid cells (ILC2s) are an immune population secreting Th2 cytokines playing a role in the regulation of adipose metabolic homeostasis. Here the authors show that engagement of GITR, a member of the TNF superfamily, in activated ILC2s is protective against insulin resistance in both a preventive and a therapeutic manner in the context of obesity.
- Lauriane Galle-Treger
- , Ishwarya Sankaranarayanan
- & Omid Akbari
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Article
| Open AccessSatb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation
A chromatin remodelling factor Satb1 is essential for T cell lineage development in the thymus. Here the authors show that while Satb1 is dispensable for the differentiation of Th17 cells and their response to gut commensals, it plays a critical role in pathogenic Th17 effector function in EAE by directly activating Bhlhe40 and modulating PD-1.
- Keiko Yasuda
- , Yohko Kitagawa
- & Keiji Hirota
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Article
| Open AccessRunx/Cbfβ complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation
Group 2 innate lymphoid cells (ILC2) are important mediators for allergy, but how ILC2 are regulated under chronic inflammation is still unclear. Here the authors show that Runx transcription factors, which normally suppresses ILC2 activation at steady state, help promote ILC2 activation and type 2 cytokine production in lung allergy mouse models.
- Chizuko Miyamoto
- , Satoshi Kojo
- & Takashi Ebihara
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Article
| Open AccessEnhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway
Urolithins are microbial metabolites derived from food polyphenols. Here, Singh et al. show that urolithin A and a synthetic analogue enhance gut barrier function via Nrf2-dependent pathways and mitigate inflammation and colitis in mice, highlighting a potential application for inflammatory bowel diseases.
- Rajbir Singh
- , Sandeep Chandrashekharappa
- & Venkatakrishna R. Jala
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Article
| Open AccessB cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation
B cells contribute to rheumatoid arthritis pathogenesis and bone erosion, but the underlying mechanisms are still unclear. Here the authors show, using mouse models and patient tissues, that B cells directly inhibit osteoblast differentiation by producing CCL3 and TNF, thereby providing a potentially new direction for arthritis therapy.
- Wen Sun
- , Nida Meednu
- & Lianping Xing
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Article
| Open AccessMacrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells
Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix degradation. Here Hadi et al. identify a netrin-1/neogenin-based crosstalk between macrophages and vascular smooth muscle cells (VSMCs), leading to the secretion of the matrix metalloproteinase MMP-3 by VSMCs and subsequent matrix degradation in AAA lesions.
- Tarik Hadi
- , Ludovic Boytard
- & Bhama Ramkhelawon
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Article
| Open AccessLUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.
- Lucia Taraborrelli
- , Nieves Peltzer
- & Henning Walczak
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Article
| Open AccessHuman Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments
At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4+ T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.
- Hiroyuki Yoshitomi
- , Shio Kobayashi
- & Junya Toguchida
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Article
| Open AccessOridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity
The small molecule oridonin (Ori) from the traditional Chinese herb Rabdosia rubescens has anti-inflammatory activity. Here the authors show that Ori can be covalently linked to NLRP3 to prevent assembly of the NLRP3 inflammasome, and to ameliorate inflammation in several mouse disease models.
- Hongbin He
- , Hua Jiang
- & Rongbin Zhou
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Article
| Open AccessA multi-modal MRI study of the central response to inflammation in rheumatoid arthritis
Many diseases, such as rheumatoid arthritis, are characterized by a chronic inflammatory state, but it is not clear whether or how this affects the brain. Here, the authors show that the severity of on-going inflammation predicts altered functional brain connectivity in people with rheumatoid arthritis.
- Andrew Schrepf
- , Chelsea M. Kaplan
- & Neil Basu
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Article
| Open AccessThe IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation
IL-33 orchestrates type 2 immunity in allergic asthma. Here the authors show, using biochemical, structural and patient data, that upon IL-33 or allergic challenge, the isomerase Pin1 modifies IRAK-M to control the production of pro-inflammatory cytokines in the setting of airway inflammation.
- Morris Nechama
- , Jeahoo Kwon
- & Kun Ping Lu
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Article
| Open AccessReduced oxidative capacity in macrophages results in systemic insulin resistance
M1-like polarization of macrophages is thought to control adipose inflammation and associated insulin resistance and metabolic syndrome. Here the authors show that macrophage-specific deletion of the OxPhos-related gene Crif1 results in an M1-like phenotype in mice, and that the effects can be reversed by recombinant GDF15.
- Saet-Byel Jung
- , Min Jeong Choi
- & Minho Shong
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Article
| Open AccessSpecies-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity
In contrast to HIV, simian immunodeficiency viruses (SIV) do not cause disease in their hosts, and the reasons for this are unclear. Here, Joas et al. incorporate two putative HIV virulence factors into SIV and study effects in infected monkeys, suggesting that species-specific host factors are responsible for HIV pathogenesis.
- Simone Joas
- , Erica H. Parrish
- & Frank Kirchhoff
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| Open AccessCalcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis
Treg cells can maintain intestinal homeostasis and limit intestinal bowel disease. Here the authors use a mouse model of spontaneous colitis to show that calcineurin-NFAT-induced IL-2 production by dendritic cells regulates the balance between Treg and effector T cells in the gut lamina propria.
- Andrea Mencarelli
- , Hanif Javanmard Khameneh
- & Alessandra Mortellaro
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Article
| Open AccessHuman Semaphorin-4A drives Th2 responses by binding to receptor ILT-4
Semaphorin-4A is a cell surface protein with known functions in neural development and immune regulation, but the mechanism for immune modulation is unclear. Here the authors show that ILT-4, previously found on myeloid cells, is the receptor of Semaphorin-4A on activate human CD4 T cells for mediating T cell co-stimulation.
- Ning Lu
- , Ying Li
- & Lieping Chen
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Article
| Open AccessThe p55TNFR-IKK2-Ripk3 axis orchestrates arthritis by regulating death and inflammatory pathways in synovial fibroblasts
TNF is a major therapeutic target for rheumatoid arthritis (RA) and synovial fibroblasts are central to the pathogenesis of RA. Here the authors dissect TNF-induced death and activation signalling in RA synovial fibroblasts and TNF-driven arthritis and indicate that a successful therapeutic strategy might be to target both IKK2 and RIPK3 at the same time.
- Marietta Armaka
- , Caroline Ospelt
- & George Kollias
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Article
| Open AccessIL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells
XLP-2 syndrome is caused by XIAP mutation. Here the authors show that mouse and human XIAP-deficient regulatory T cells have defective suppressive function as a result of conversion to proinflammatory cytokine producing cells, an effect that can be prevented by blocking the IL-6 receptor.
- Wan-Chen Hsieh
- , Tzu-Sheng Hsu
- & Ming-Zong Lai
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Article
| Open AccessAngiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours
Circulating myeloid cells can leave the vasculature to infiltrate tumours and are thought to contribute to tumour angiogenesis. Here the authors live image monocytes that migrate to xenograft tumours and map an extravasation cascade of human proangiogenic monocytes into the tumour.
- Adama Sidibe
- , Patricia Ropraz
- & Beat A. Imhof
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Article
| Open AccessHepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
During obesity, chronic inflammation leads to insulin resistance and diabetes. Here, Brenachot et al. show that Protein Tyrosine Phosphatase Receptor Gamma is upregulated in obesity by inflammatory signals and correlates with insulin resistance in humans. Its deletion in mouse models of obesity and inflammation ameliorates insulin resistance by suppressing glucose production.
- Xavier Brenachot
- , Giorgio Ramadori
- & Roberto Coppari
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Article
| Open AccessVSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism
Macrophage differentiation and inflammatory function are controlled by cell metabolism. Here, the authors use a viral hepatitis model and a high-fat diet model of insulin resistance to show how VSIG4 inhibits inflammatory macrophage activation by modulating mitochondrial pyruvate metabolism.
- Jialin Li
- , Bo Diao
- & Yuzhang Wu
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Article
| Open AccessSensing and responding to allergic response cytokines through a genetically encoded circuit
The standard treatment for an allergic response is anti-histamines, steroids and anti-IgE antibodies. Here the authors present a genetic circuit that senses IL-4 and IL-13 and responses with DARPin production to bind IgE.
- Hélène Chassin
- , Barbara Geering
- & Martin Fussenegger
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Article
| Open AccessMacrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation
VLDLR regulates cellular lipoprotein uptake and storage. Here, the authors show that VLDLR, expressed on adipose tissue macrophages, is upregulated in obesity and promotes adipose tissue inflammation by upregulating ceramide production and facilitating M1-like macrophage polarization.
- Kyung Cheul Shin
- , Injae Hwang
- & Jae Bum Kim
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Article
| Open AccessTranscription factor Foxo1 is essential for IL-9 induction in T helper cells
The transcription factor Foxo1 can control regulatory T cell and Th1 function. Here the authors show that Foxo1 is also critical for IL-9 production by Th9 cells and other IL-9-producing cells.
- Sakshi Malik
- , Srikanth Sadhu
- & Amit Awasthi
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Article
| Open AccessE3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP
Prolonged NOD2 ligand engagement induces tolerance and attenuated NOD2 signalling, but the molecular mechanisms leading to this tolerance induction are unclear. Here the authors show that the degradation of a NOD2 adaptor, RIP2, by the E3 ligase ZNRF4 is essential for the down-regulation of NOD2 signalling.
- Pradeep Bist
- , Wan Shoo Cheong
- & Bindu Sukumaran
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Article
| Open AccessIL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression
NOTCH signalling stimulates oligodendrocyte progenitor cell proliferation but how this regulates demyelinating disease is unclear. Here, the authors show that an IL-17 adaptor protein, Act1, interacts with the C-terminal fragment of NOTCH1 (NICD) to activate cell proliferation and an inflammatory response.
- Chenhui Wang
- , Cun-Jin Zhang
- & Xiaoxia Li
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Article
| Open AccessTemporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance
Interleukin-6 (IL-6) is increased in obesity and activates T cells to promote inflammation. Here, Xuet al. use mice that lack IL-6 receptors on T cells to uncover the temporal and tissue-specific effects of classic and trans IL-6 signalling on inflammation and insulin resistance on a high-fat diet.
- Elaine Xu
- , Mafalda M. A. Pereira
- & Jens C. Brüning
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Article
| Open AccessTNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling
Reduced BMP receptor II signalling underlies pulmonary arterial hypertension (PAH). Here, Hurstet al. show that TNFα subverts BMP signalling by increasing BMP6 expression and signalling via an alternative BMP receptor, ALK2, in pulmonary artery smooth muscle cells to drive abnormal proliferation and PAH.
- Liam A. Hurst
- , Benjamin J. Dunmore
- & Nicholas W. Morrell
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Article
| Open AccessThe microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner
γδ T cells are major producers of IL-17A in response to microbial infection. Here the authors show that a high load of commensal microbes can maintain homeostasis of IL-17A+γδ T cells in the liver via CD1d antigen presentation, with implications for liver diseases.
- Fenglei Li
- , Xiaolei Hao
- & Zhigang Tian
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Article
| Open AccessA TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice
TNFSF14 (LIGHT) contributes to airway inflammation and remodelling. Here the authors show that TNFSF14 acting on its receptor TNFRSF14 on mast cells enhances their IgE-dependent activation and that interference with this pathway attenuates features of asthma pathology in mice.
- Riccardo Sibilano
- , Nicolas Gaudenzio
- & Stephen J. Galli
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Article
| Open AccessAltered intestinal microbiota–host mitochondria crosstalk in new onset Crohn’s disease
Crohn’s disease is associated with altered intestinal microbiota. Here, the authors show that the microbe Atopobium parvulumis associated with Crohn’s disease patients, triggers colitis in a mouse model, and that scavenging microbe-induced hydrogen sulfide improved symptoms in mice.
- Walid Mottawea
- , Cheng-Kang Chiang
- & Alain Stintzi
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Article
| Open AccessThe persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis
Chronic low-grade inflammation has been suspected to promote atherosclerosis. Here, Geng et al. show that sustained low-grade inflammation promotes atherosclerosis in mice via monocyte programing that involves a coupled disruption of IRAK-M regulation and induction of miR-24.
- Shuo Geng
- , Keqiang Chen
- & Liwu Li
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Article
| Open AccessThe Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation
Aberrant activation of the IgE receptor on mast cells leads to allergic responses. Here, the authors identify an E3 ligase and adaptor protein that can reduce IgE signalling by targeting phosphorylated-Syk for degradation.
- Kwok Ho Yip
- , Natasha Kolesnikoff
- & Michele A. Grimbaldeston