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| Open AccessA20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation
As resident macrophages of the brain, microglia are important for neuroinflammatory responses. This work shows that nuclear factor kappa B regulatory protein A20 is important for microglia activation and regulation during inflammation of the central nervous system.
- Sofie Voet
- , Conor Mc Guire
- & Geert van Loo
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Article
| Open AccessWASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis
Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.
- Amlan Biswas
- , Dror S. Shouval
- & Scott B. Snapper
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Article
| Open AccessIL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet+ B cells in SLE
Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear. Here the authors show that a CD11chiT-bet+ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.
- Shu Wang
- , Jingya Wang
- & Rachel Ettinger
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Article
| Open AccessObesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment
Inflammation can be induced by obesity, and has been linked with onset of colorectal cancer (CAC). Here the authors show in mouse models that obesity-induced interleukin-6 alters macrophage function to enhance CCL-20/CCR-6-mediated recruitment of B cells and γδ T cells, thereby promoting gut inflammation and CAC progression.
- Claudia M. Wunderlich
- , P. Justus Ackermann
- & F. Thomas Wunderlich
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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 AccessRedefining the ancestral origins of the interleukin-1 superfamily
The IL-1 evolutionary history is essential in our understanding of function and development. Here the authors use molecular phylogenetic analysis to probe the IL-1 family in a range of species, suggesting disparate phylogenetic association of IL-18 and IL-33 proteins within the IL-1 family.
- Jack Rivers-Auty
- , Michael J. D. Daniels
- & David Brough
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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 AccessA dual role for the N-terminal domain of the IL-3 receptor in cell signalling
The N-terminal domain (NTD) of interleukin-3 receptor α-subunit (IL3Rα) is involved in IL-3 recognition but the underlying mechanism is unknown. Here, the authors present crystal structures of the IL3Rα complex and provide biochemical evidence that the NTD regulates IL-3 binding and signalling complex assembly.
- Sophie E. Broughton
- , Timothy R. Hercus
- & Michael W. Parker
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Article
| Open AccessHypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease
B cells are important for antigen presentation and antibody production in humoral immunity, but are also increasingly recognized for their immune regulatory functions. Here the authors show that HIF-1α, a hypoxia-induced transcription factor, is important for controlling IL-10 induction in and immune-suppressive activity of B cells.
- Xianyi Meng
- , Bettina Grötsch
- & Aline Bozec
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Article
| Open AccessInteraction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability
SOCS3 is an important negative feedback inhibitor of JAK–STAT-mediated cytokine signalling. Here the authors implicate cavin-1 — an essential component of caveolae — in the recruitment of SOCS3 to the plasma membrane to prevent sustained cytokine receptor signalling.
- Jamie J. L. Williams
- , Nasser Alotaiq
- & Timothy M. Palmer
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Article
| Open AccessRegulatory T cells control toxicity in a humanized model of IL-2 therapy
High dose IL-2 is a viable treatment option for cancer immune therapy, but the underlying mechanism for the accompanying undesirable morbidity is unclear. Here the authors show, using human immune system mouse models, that regulatory T cells and their functions on effector T cells are essential modulators of the related pathogenesis.
- Yan Li
- , Helene Strick-Marchand
- & James P. Di Santo
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Article
| Open AccessIL-2 imprints human naive B cell fate towards plasma cell through ERK/ELK1-mediated BACH2 repression
T cells help B cells to differentiate into antibody-producing plasma cells. Here the authors show that T cells produce interleukin-2 to activate ERK/ELK1 and suppress BACH2 expression by modulating the BACH2 super-enhancer, thereby altering BACH2 downstream transcription programs for plasma cell differentiation.
- Nicolas Hipp
- , Hannah Symington
- & Céline Delaloy
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Article
| Open AccessTristetraprolin inhibits macrophage IL-27-induced activation of antitumour cytotoxic T cell responses
IL-27 is one of a number of cytokines that can induce antitumour CD8+ T cell responses. Here the authors show that TTP, encoded by Zfp36, degrades p28 to inhibit IL-27 production by macrophages and is thereby a negative regulator of the antitumour response.
- Qinghong Wang
- , Huan Ning
- & Jianguo Liu
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Article
| Open AccessIL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease
IL-12p35 is common to IL-35 and IL-12, which have opposing effects on inflammation. Here the authors show that the IL-12p35 subunit induces regulatory B cells and can be used therapeutically to limit autoimmune uveitis in mice.
- Ivy M. Dambuza
- , Chang He
- & Charles E. Egwuagu
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Article
| Open AccessNeutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage
Neutrophils are important modulators of tissue damage after intracerebral hemorrhage (ICH), but how this function is regulated is not clear. Here, the authors show interleukin-27 promotes the tissue-protecting functions of neutrophils via, at least partly, the induction of lactoferrin to present a potential therapy for ICH.
- Xiurong Zhao
- , Shun-Ming Ting
- & Jaroslaw Aronowski
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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 AccessTargeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity
How NALP7 inflammasome formation is regulated is unclear. Here the authors show that STAMBP prevents lysosomal degradation of NALP7 and present BC-1471 as a potential therapeutic STAMBP inhibitor, showing it can reduce TLR-induced IL-1β production.
- Joseph S. Bednash
- , Nathaniel Weathington
- & Rama K. Mallampalli
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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 AccessIL-15 sustains IL-7R-independent ILC2 and ILC3 development
ILC2 and ILC3 are generally thought to require IL-7. Here the authors use IL-7 ko mice and provide side-by-side comparison of ILCs from different tissues to show that IL-7 signalling is not required for intestinal ILC maintenance or function and that IL-15 can compensate for absence of IL-7.
- Michelle L. Robinette
- , Jennifer K. Bando
- & Marco Colonna
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Article
| Open AccessRegulation of phagocyte triglyceride by a STAT-ATG2 pathway controls mycobacterial infection
Cytokines and their associated pathways can affect survival ofMycobacterium tuberculosis in macrophages, representing potential targets for host-directed therapies. Here, Péan et al. show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplet homeostasis.
- Claire B. Péan
- , Mark Schiebler
- & Marc S. Dionne
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Article
| Open AccessA mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis
In patients with cystic fibrosis, IL-9 signalling is increased. The authors describe an inflammatory loop in which IL-9 produced by Th9 cells drives mast cells to produce IL-2, resulting in ILC2 cell activation, and show inhibition of this loop with blocking antibodies to IL-9 in a mouse model of pulmonary infection.
- Silvia Moretti
- , Giorgia Renga
- & Luigina Romani
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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 AccessInterleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis
Natural killer homeostasis is thought to be governed by gamma chain cytokines including IL-15. Here, the authors show that IL-12 can trigger the development of a distinct subset of natural killer cells with anti-tumour activity.
- Isabel Ohs
- , Maries van den Broek
- & Burkhard Becher
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Article
| Open AccessA TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice
Tolerance is required to prevent rejection of intrahepatic islet allografts as a potential treatment for type 1 diabetes. Here the authors show that IL-22 produced by NK1.1+cells in the liver of streptozotocin T1D model mice can drive tolerance to allografted islets.
- Deepak Tripathi
- , Sambasivan Venkatasubramanian
- & Ramakrishna Vankayalapati
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Article
| Open AccessThe E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3
The NLRP3 inflammasome controls the response of the host to pathogens; precise regulation is required to limit autoimmune diseases. Here, the authors identify the E3 ligase TRIM31 that aids the ubiquitin-mediated proteasomal degradation of NLRP3, which may be a therapeutic target for alleviating disease.
- Hui Song
- , Bingyu Liu
- & Wei Zhao
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Article
| Open AccessIL-12 protects from psoriasiform skin inflammation
IL-12 and IL-23 share the common p40 subunit yet have distinct immunological functions with IL-12 typically contributing to Th1 responses and IL-23 to Th17 responses. Here the authors show that current p40 based therapies for psoriasis are counterproductive owing to an IFN-γ-independent tissue protective function of IL-12 in skin.
- Paulina Kulig
- , Stephanie Musiol
- & Burkhard Becher
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| Open AccessMacrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice
Ventricular arrhythmia is a leading cause of death in patients with diabetes. Here the authors show that inflammasome activation and ILK-1β production in cardiac macrophages cause arrhythmia in diabetic mice, which can be successfully treated using agonists to IL-1β receptor or NLRP3 inhibitors.
- Gustavo Monnerat
- , Micaela L. Alarcón
- & Emiliano Medei
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Article
| Open AccessTiam1/Rac1 complex controls Il17a transcription and autoimmunity
Tiam1 is a guanine nucleotide exchange factor for the Rho-family GTPase Rac1. Here, the authors show that nuclear Tiam1 and Rac1 bind to RORγt on the IL-17 promoter, activating its transcription, and that inhibiting Tiam1/Rac1 is beneficial in a mouse model of autoimmunity.
- Ahmed T. Kurdi
- , Ribal Bassil
- & Wassim Elyaman
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Article
| Open AccessLoss of immune tolerance to IL-2 in type 1 diabetes
Type 1 diabetes is driven by T-cell autoimmunity to pancreatic islet cells. Here the authors show that autoreactive anti-IL-2 T and B cells are present in type 1 diabetes patients, and that anti-IL-2 antibodies precede diabetes onset in mice, suggesting their potential as a diagnostic marker.
- Louis Pérol
- , John M. Lindner
- & Eliane Piaggio
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Article
| Open AccessCARD9 negatively regulates NLRP3-induced IL-1β production on Salmonella infection of macrophages
IL-1β is important for control of bacterial infections, but when deregulated can lead to excessive inflammation. The authors show that the adaptor protein CARD9 suppresses levels of IL-1β and is downregulated during S. Typhimuriuminfection, thus facilitating an inflammatory response
- Milton Pereira
- , Panagiotis Tourlomousis
- & Clare E. Bryant
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| Open AccessSelective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy
High-affinity IL-2Rα expressed by Tregs mitigates the potential of IL-2 use in cancer therapy. Here, the authors fuse IL-2 with an NKDG2 binding domain, and show that it induces IL-2 signalling selectively in NKG2D+cells, delaying tumour growth in mice without the side effects of conventional IL-2 therapy.
- Reza Ghasemi
- , Eric Lazear
- & Alexander Sasha Krupnick
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Article
| Open AccessIL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses
Chitinase 3-like 1 regulates cell death, inflammation and tissue remodelling via IL-13receptorα2. Here, the authors show that TMEM219 is a IL-13Rα2 co-receptor and modulates oxidant-induced apoptosis and lung injury, melanoma metastasis and TGF-β1 signalling, downstream of Chi3l1-IL-13Rα2.
- Chang-Min Lee
- , Chuan Hua He
- & Jack A. Elias
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Article
| Open AccessNK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation
IL-15 orchestrates NK cell metabolism, proliferation, and activation. Here the authors show that Tsc1 is dispensable for mature NK cells but is critical for survival of immature NK by preventing their exhaustive proliferation and activation downstream of IL-15.
- Meixiang Yang
- , Shasha Chen
- & Zhongjun Dong
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Article
| Open AccessIL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin
Epidermal intraepithelial lymphocytes (IEL) produce IL-13, but the physiological role of this cytokine production is not clear. Here the authors show that IEL-production of IL-13 is a vital lymphoid stress surveillance mechanism driving crosstalk with epithelial cells to maintain tissue homeostasis and inhibit chemical carcinogenesis in mice.
- Tim Dalessandri
- , Greg Crawford
- & Jessica Strid
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Article
| Open AccessNFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells
Regulatory B cells are important for preventing skin autoimmunity. Here the authors show that NFATc1 suppresses IL-10 transcription in regulatory B cells, and inhibiting NFATc1 decreases immunopathology in a mouse model of imiquimod-induced skin inflammation.
- Hani Alrefai
- , Khalid Muhammad
- & Edgar Serfling
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Article
| Open AccessVirtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner
Virtual memory T cells are CD8 T cells with memory phenotype present in unimmunized mice. Here the authors show that these cells have higher affinity for self-antigen, depend on IL-15 for proliferation and antigen-non-specific cytotoxicity in mice, and that a similar population exists in humans.
- Jason T. White
- , Eric W. Cross
- & Ross M. Kedl
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Article
| Open AccessInduction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis
Interleukin-25 has been reported to have anticancer activity with very little effect on non-malignant cells. Here, the authors show that a synthetic phytochemical can be used to induce the secretion of Interleukin-25 from tumour associated fibroblasts resulting in impaired tumour metastasis.
- Shu-Yi Yin
- , Feng-Yin Jian
- & Ning-Sun Yang
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Article
| Open AccessIL-15-dependent balance between Foxp3 and RORγt expression impacts inflammatory bowel disease
Transcription factors directing T cell fate are induced by instructive signals such as cytokines. Here the authors show that IL-15 promotes Foxp3 and inhibits RORγt expression in CD4 T cells, and that IL-15 is critical to suppress colitis by maintaining the Treg to Th1/Th17 ratio in a mouse model.
- Milena J. Tosiek
- , Laurence Fiette
- & Antonio A. Freitas
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Article
| Open AccessIL-17-producing γδ T cells enhance bone regeneration
γδ T cells are innate-like lymphocytes that regulate immune responses by producing IL-17A or IFN-γ, but have no known role in bone healing. Here the authors show a nonimmune bone-regenerative function of IL-17A produced by the Vγ6+ subset in mice.
- Takehito Ono
- , Kazuo Okamoto
- & Hiroshi Takayanagi
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Article
| Open AccessIL-7 signalling represses Bcl-6 and the TFH gene program
It remains incompletely understood how cytokines shape TH1 cell differentiation to central memory T (TCM) and follicular T helper (TFH) cells. Here the authors show that TH1 cells can co-initiate the expression of both TFH and TCM gene programs and that IL-7 signalling represses TFH-associated but not TCM-associated genes.
- Paul W. McDonald
- , Kaitlin A. Read
- & Kenneth J. Oestreich
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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 AccessOxidation of the alarmin IL-33 regulates ST2-dependent inflammation
IL-33, released by epithelial cells in response to stress, is a potent activator of inflammation. Here Cohenet al. show that secreted IL-33 is rapidly inactivated by disulfide bond formation that prevents binding to its receptor, and that IL-33-related cytokines are susceptible to similar oxidation.
- E. Suzanne Cohen
- , Ian C. Scott
- & Tomas Mustelin
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Article
| Open AccessBatf is important for IL-4 expression in T follicular helper cells
T follicular helper cells are a distinct subtype of CD4 T helper cells, which contributes to the regulation of type 2 humoral immunity by producing IL-4. Here, the authors identify Batf as an important transcription factor regulating IL-4 expression in T follicular helper cells but not in Th2 cells.
- Anupama Sahoo
- , Andrei Alekseev
- & Roza Nurieva
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Article
| 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
| Open AccessIL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection
HIV-infected patients who maintain undetectable virus levels possess elevated plasma concentrations of IL-21. Here, Adoroet al. show that IL-21 inhibits early viral infection in humanized mice and suppresses HIV-1 replication in vitroby upregulating a microRNA via the regulatory protein STAT3.
- Stanley Adoro
- , Juan R. Cubillos-Ruiz
- & Laurie H. Glimcher
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Article
| Open AccessIL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells
Control of γδ T-cell activation remains incompletely understood. Here the authors show that during autoimmune arthritis development αβ CD4+T cells recruit a subset of IL-17-producing γδ T cells to the joints, and that both components are essential to cause pathology in a mouse model of the disease.
- Aoi Akitsu
- , Harumichi Ishigame
- & Yoichiro Iwakura
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IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis
Innate immune responses are regulated in the intestine to prevent excessive inflammation. Here the authors demonstrate a pivotal role for intestinal macrophages that constitutively produce IL-10 in controlling excessive innate immune activation and preventing tissue damage after an acute bacterial infection.
- Petra Krause
- , Venetia Morris
- & Masako Murai
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Article
| Open AccessLRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis
Macrophages activate gene expression of alternative activation program in response to IL-13. Here the authors show that Liver Receptor Homologue-1 regulates synthesis of lipid metabolites stimulating antifungal and repressing proinflammatory genes in macrophages exposed to IL-13 through PPAR activation.
- Lise Lefèvre
- , Hélène Authier
- & Agnès Coste
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Article
| Open AccessMicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease
Collagen 3 is increased during tendon repair, but is then replaced by Collagen 1 that has superior biomechanical properties. Here the authors show that IL-33 is induced by tendon damage and regulates miR-29a, which controls Collagen 3 production and feeds back on IL-33, orchestrating tendon repair.
- Neal L. Millar
- , Derek S. Gilchrist
- & Iain B. McInnes