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IκBβ enhances the generation of the low-affinity NFκB/RelA homodimer
The NFκB signalling pathway is regulated through the formation of transcription factor dimers but mechanisms controlling their formation are poorly understood. Here, Tsui et al. report that IκBb is a positive regulator of Rel-NFκB dimer formation, using in vitro and in vivoexperiments and mathematical modelling.
- Rachel Tsui
- , Jeffrey D. Kearns
- & Alexander Hoffmann
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| Open AccessNFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma
The role of neutrophils in cancer development is not widely appreciated. Here, the authors show that NF-κB-deficient hepatocytes overproduce chemokines, leading to hepatocellular carcinoma due to excessive neutrophil recruitment, and that neutrophil depletion prevents liver cancer in these mice.
- C. L. Wilson
- , D. Jurk
- & D. A. Mann
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The acetyltransferase HAT1 moderates the NF-κB response by regulating the transcription factor PLZF
The importance of the post-translational modification by acetylation in regulating protein function is not fully understood. Here, the authors show that acetylation of the transcriptional factor PLZF promotes the assembly of a repressor complex that limits the inflammatory response mediated by NF-κB.
- Anthony J. Sadler
- , Bandar A. Suliman
- & Dakang Xu
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| Open AccessQuantitative analysis of the TNF-α-induced phosphoproteome reveals AEG-1/MTDH/LYRIC as an IKKβ substrate
Inflammatory cytokines such as TNF-α influence inflammation, apoptosis and tumour development through regulation of the kinase IKKβ. Krishnan and Nolte et al.apply quantitative proteomics to identify potential IKKβ targets, and reveal phosphorylation of AEG-1 by IKKβ as a mechanism controlling NF-κB signalling.
- Ramesh K. Krishnan
- , Hendrik Nolte
- & Jakub M. Swiercz
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| Open AccessThe interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation
Human papillomavirus employs immune evasion strategies to establish a long-term infection. Here the authors show that the virus in the EGFR-dependent manner induces IFRD1, which blocks NFκB activating acetylation, and that this process can be suppressed by the EGFR inhibitor cetuximab.
- Bart Tummers
- , Renske Goedemans
- & Sjoerd H. van der Burg
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| Open AccessComplement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling
The role of macrophages in hypertension-induced arterial remodeling is poorly understood. Here, Sumida et al. show that high blood pressure drives the alternatively activated macrophages to secrete complement C1q protein, which in turn elicits proliferative β-catenin signalling in the arterial smooth muscle cells.
- Tomokazu Sumida
- , Atsuhiko T. Naito
- & Issei Komuro
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Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages
Activation of Toll-like receptors induces inflammation, which is critical for defence against infection but can cause autoimmunity, and thus needs tight regulation. Here, the authors show that TRAF2 limits inflammatory responses downstream of these receptors by inducing degradation of IRF5 and c-Rel.
- Jin Jin
- , Yichuan Xiao
- & Shao-Cong Sun
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| Open AccessFc gamma receptor-TLR cross-talk elicits pro-inflammatory cytokine production by human M2 macrophages
M2-polarized macrophages are generally considered anti-inflammatory, but whether polarization markers always reflect functional states remains debatable. Here the authors show that complexed IgG and TLR co-stimulation, observed in infections or rheumatoid arthritis, elicits an inflammatory response in M2 macrophages.
- Lisa T. C. Vogelpoel
- , Ivo S. Hansen
- & Jeroen den Dunnen
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| Open AccessCharacterizing the genetic basis of innate immune response in TLR4-activated human monocytes
Toll-like receptors (TLRs) are an essential component of innate immunity. Here, the authors identify expression quantitative trait loci that are unique to TLR4-stimulation and highlight genes that may have a role in innate immune response.
- Sarah Kim
- , Jessica Becker
- & Johannes Schumacher
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The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity
T-cell activation is controlled by signalling through the T-cell receptor and other molecules. Here the authors show that Med23 is a negative regulator of T-cell activation at a transcriptional level and that Med23 deficiency in T cells results in development of autoimmunity in aged mice.
- Yang Sun
- , Xiaoyan Zhu
- & Xiaolong Liu
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| Open AccessNAD+ protects against EAE by regulating CD4+ T-cell differentiation
The mechanism by which NAD+ alters the systemic immune response is unclear. Here the authors show that NAD+ induces systemic homeostasis and protects against experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, by regulating CD4+T cell differentiation and promoting myelin and axonal regeneration.
- Stefan G. Tullius
- , Hector Rodriguez Cetina Biefer
- & Abdallah ElKhal
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Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production
Dendritic cells (DCs) initiate distinct arms of immunity in response to different classes of pathogens. Here Gringhuis et al. show that DCs produce IL-27 upon sensing fucose-containing pathogen ligands via DC-SIGN, promoting follicular T helper cell differentiation and antibody production.
- Sonja I. Gringhuis
- , Tanja M. Kaptein
- & Teunis B. H. Geijtenbeek
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IKKα negatively regulates ASC-dependent inflammasome activation
The molecular mechanisms mediating inflammasome activation are not fully elucidated. Here the authors show that the kinase IKKα interacts in the nucleus and perinuclear area with the adaptor molecule ASC, negatively regulating inflammasome activation.
- Bradley N. Martin
- , Chenhui Wang
- & Xiaoxia Li
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Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9
ß-TrCP is an adaptor protein that controls activity of several key regulatory proteins including NFκB by ubiquitin-mediated proteolysis. Here Shi et al. demonstrate that ß-TrCP is negatively regulated by the brain-specific protein TRIM9, limiting activation of NFκB and production of proinflammatory cytokines.
- Mude Shi
- , Hyelim Cho
- & Jae U. Jung
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Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity
Mitochondria modulate the innate immune response of infected cells against RNA viruses such as influenza. Here Yoshizumi et al.show that an influenza A viral protein, PB1-F2, interferes with such response by inducing mitochondrial fragmentation and altering the RIG-I and NLRP3 innate immune pathways.
- Takuma Yoshizumi
- , Takeshi Ichinohe
- & Takumi Koshiba
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| Open AccessToll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated inflammatory monocyte migration
Inflammatory monocytes play an important role in host defense against infections. Here the authors provide insights into the mechanism behind the recruitment of inflammatory monocytes to sites of infection by demonstrating the involvement of Toll-like receptor 4 and MAIR-II immunoreceptors in this process.
- Naoya Totsuka
- , Yun-Gi Kim
- & Akira Shibuya
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Switching between humoral and cellular immune responses in Drosophila is guided by the cytokine GBP
Insects combat infection using humoral and cellular immunity but it is not fully understood how these mechanisms are coordinated. Here, using Drosophilaas a model, the authors show that the PDGF- and VEGF-receptor homologue (Pvr) can direct the nature of innate immune responses expressed by hematocytes.
- Seiji Tsuzuki
- , Hitoshi Matsumoto
- & Yoichi Hayakawa
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| Open AccessRasGRP3 limits Toll-like receptor-triggered inflammatory response in macrophages by activating Rap1 small GTPase
Toll like receptors (TLRs) couple microbial sensing to initiation of immune responses, which are essential for defense against pathogens but may cause immunopathology when activated excessively. Here the authors show that RasGRP3 sets a threshold of TLR activation to prevent immunopathology.
- Songqing Tang
- , Taoyong Chen
- & Jianli Wang
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Jarid2 is induced by TCR signalling and controls iNKT cell maturation
The transcriptional regulator PLZF controls many of the key effector functions of invariant natural killer T (iNKT) cells but it is not clear how PLZF itself is regulated. Here, Pereira et al. demonstrate that a methlytransferase Jarid2 regulates PLZF expression and thus controls iNKT cell maturation.
- Renata M. Pereira
- , Gustavo J. Martinez
- & Anjana Rao
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| Open AccessHGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance
HGK kinase is involved in signalling in many cell types but its function in T cells remains unclear. Here, using T-cell-specific HGK knockout mice, the authors show that HGK prevents the development of systemic inflammation and insulin resistance by inhibiting production of the proinflammatory cytokines IL-6 and IL-17.
- Huai-Chia Chuang
- , Wayne H. -H. Sheu
- & Tse-Hua Tan
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NEDD4 ubiquitinates TRAF3 to promote CD40-mediated AKT activation
The costimulatory molecule CD40 expressed on B cells has an important role in B cell-mediated immunity but some aspects of CD40-mediated signalling remain unknown. Here the authors show that the ubiquitin ligase NEDD4 is a part of a CD40 signalling complex required for CD40-induced Akt activation.
- Di-Feng Fang
- , Kun He
- & Wei-Hua Li
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LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria
The immune system plays an important role in preventing microbial colonization in the urinary tract but the mechanism of this protection is not completely understood. Here, the authors identify LRRC19 expressed in the kidneys as a pathogen-recognition receptor involved in the immune response to uropathogenic bacteria.
- Xiaomin Su
- , Siping Min
- & Rongcun Yang
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IL-23 promotes TCR-mediated negative selection of thymocytes through the upregulation of IL-23 receptor and RORγt
Negative selection of double-positive thymocytes that express autoreactive T-cell receptors plays a crucial role in the maintenance of self-tolerance. Here, the authors provide evidence that the cytokine IL-23 produced by thymic dendritic cells is involved in the depletion of double-positive thymocytes.
- Hao Li
- , Hui-Chen Hsu
- & John D. Mountz
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Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6T17 cells in health and inflammation
Skin-resident IL-17-producing γδT cells have an important role in skin inflammation but their development and trafficking is not well established. Here, Cai et al. unveil differences in the developmental requirements and functional regulation of two subsets of dermal γδT cells.
- Yihua Cai
- , Feng Xue
- & Jun Yan
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Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment
The standard treatment for hepatitis C virus (HCV) infection, combining interferon (IFN) α and ribavirin, fails in a number of patients. Here, the authors use a mathematical model of the IFN signalling network in the presence of HCV to explain the success or failure of hepatitis C treatment.
- Pranesh Padmanabhan
- , Urtzi Garaigorta
- & Narendra M. Dixit
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An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells
Contact hypersensitivity is caused by the reaction of T cells to various chemical contact allergens. Here, the authors unveil the signalling pathway induced in dendritic cells in response to contact allergens, which is required for the stimulation of T-cell sensitization in contact hypersensitivity.
- Shinsuke Yasukawa
- , Yoshiyuki Miyazaki
- & Hiromitsu Hara
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IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1
Autoimmune diseases are regulated by the balance between pro- and anti-inflammatory cytokines. Here, the authors show that the transcriptional regulator Blimp1 is induced in inflammatory T helper cells by the cytokines IL-27 and IL-12 to counteract pro-inflammatory IL-23 and promote resolution of tissue inflammation.
- Christina Heinemann
- , Sylvia Heink
- & Thomas Korn
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IL-21 induces IL-22 production in CD4+ T cells
The cytokine interleukin-22 maintains the integrity of the colonic epithelium during inflammation. Here, the authors show that IL-21 regulates the production of IL-22 in T cells and this mechanism plays a protective role in a mouse model of colitis.
- Ada Yeste
- , Ivan D. Mascanfroni
- & Francisco J Quintana
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MicroRNA-302b augments host defense to bacteria by regulating inflammatory responses via feedback to TLR/IRAK4 circuits
Bacterial infection stimulates a powerful inflammatory response that must be regulated to prevent tissue damage. Zhou et al.identify microRNA-302b as a feedback suppressor of inflammatory signalling that alleviates lung injury following Pseudomonas infection by targeting the NF-κB activator IRAK4.
- Xikun Zhou
- , Xuefeng Li
- & Min Wu
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The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck
JNK pathway-associated phosphatase (JKAP) is a dual-specificity phosphatase known to regulate substrates in several signalling cascades. Here, Li et al. demonstrate that JKAP has a key role in negative regulation of proximal T-cell receptor signalling and suppression of T-cell-mediated autoimmunity.
- Ju-Pi Li
- , Chia-Yu Yang
- & Tse-Hua Tan
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p85α recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression
Apoptotic cell clearance is important for the maintenance of immune homeostasis. Here, Tian et al. reveal how a phosphatidylserine (PS) receptor participates in the clearance of apoptotic cells, and show that loss of the receptor can lead to autoimmunity.
- Linjie Tian
- , Seung-Chul Choi
- & John E. Coligan
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| Open AccessIntegrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages
The signalling pathways that confer differences in the responses of dendritic cells and macrophages to LPS remain poorly understood. Here, Ling et al.report that the integrin C11b is required for LPS-induced TLR4 trafficking and signalling in dendritic cells but not in macrophages.
- Guang Sheng Ling
- , Jason Bennett
- & Marina Botto
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Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade
Thymic stromal lymphopoietin is an important initiator of Th2 responses, but, to date, little is known about how it drives the immune cascade in the tissue microenvironment in vivo. Here, the authors show that skin thymic stromal lymphopoietin orchestrate interactions between immune cells, leading to Th2 priming.
- Juan Manuel Leyva-Castillo
- , Pierre Hener
- & Mei Li
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Integrin CD11b negatively regulates BCR signalling to maintain autoreactive B cell tolerance
Polymorphisms in the integrin gene CD11bare associated with susceptibility to systemic lupus erythematosus, but how this relates to the function of this integrin has not been fully investigated. Here, the authors report that CD11b has a role in the intrinsic maintenance of autoreactive B cell tolerance by regulating BCR signalling.
- Chuanlin Ding
- , Yunfeng Ma
- & Jun Yan
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Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation
Allergic airway inflammation in asthma can be treated with corticosteroids, but some patients remain unresponsive to this therapy. Here, Kabata et al. show that thymic stromal lymphopoietin contributes to the corticosteroid resistance during airway inflammation through its action on natural helper cells.
- Hiroki Kabata
- , Kazuyo Moro
- & Koichiro Asano
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Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen
Pathogen-associated molecular patterns are involved in the initiation of anti-pathogen immunity but their importance for sustaining this response is not established. Here, the authors show that persistent presence of pathogen-associated molecular patterns is required to maintain robust immune responses to pathogens.
- Samarchith P. Kurup
- & Rick L. Tarleton
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Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway
Sepsis in patients is often accompanied by thrombocytopenia, but the exact role of platelets in the pathogenesis of septicaemia has not been elucidated. Here, Xiang et al. present evidence that platelets may act as anti-inflammatory cells and protect from septic shock.
- Binggang Xiang
- , Guoying Zhang
- & Zhenyu Li
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Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state
SIRPα is an anti-inflammatory signalling receptor expressed on neutrophils. Here Zenet al.show that during inflammation, SIRPα signalling is inhibited by cleavage of its intracellular signalling motif.
- Ke Zen
- , Yalan Guo
- & Yuan Liu
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Article
| Open AccessLRRFIP2 negatively regulates NLRP3 inflammasome activation in macrophages by promoting Flightless-I-mediated caspase-1 inhibition
Inflammasomes promote the maturation of inflammatory cytokines in response to signals associated with damage and infection, but it remains unclear how these signals are attenuated. Here, the authors show that the NLRP3 inflammasome is inhibited by LRRFIP2 through recruitment of the protein Flightless I.
- Jing Jin
- , Qian Yu
- & Xuetao Cao
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NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype
Aggressive types of breast cancer often exhibit constitutive activation of the pro-inflammatory transcription factor NF-κB. Here, Yamamoto et al. show that, in basal-like breast cancer, NF-κB upregulates the Notch receptor ligand JAG1 in non-cancer stem cells and thereby induces proliferation of breast cancer stem cells.
- Mizuki Yamamoto
- , Yuu Taguchi
- & Jun-ichiro Inoue
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Thymosin β4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing
Hydrogen peroxide attracts immune cells and induces wound inflammation. Evans et al. show that hydrogen peroxide also leads to the production of thymosin β4–sulfoxide in zebrafish wounds and in mouse hearts after myocardial infarction, where it acts as an anti-inflammatory factor that promotes wound healing.
- Mark A. Evans
- , Nicola Smart
- & Paul R. Riley
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B7-H5 costimulates human T cells via CD28H
The end-result of stimulation of T-cell receptors by antigen is in part determined by co-signalling pathways such as the B7/CD28 axis. Zhu et al.identify a novel costimulatory CD28-like receptor and ligand pathway in human T cells.
- Yuwen Zhu
- , Sheng Yao
- & Lieping Chen
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Sam68 modulates the promoter specificity of NF-κB and mediates expression of CD25 in activated T cells
The NF-κB complex is a core regulator of inflammatory gene expression and activates transcription of many different target genes. Fu et al. show that NF-κB promoter specificity can be tuned by Sam68, which is required for targeting NF-κB to the CD25 promoter during T cell activation.
- Kai Fu
- , Xin Sun
- & Fengyi Wan
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High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway
CpG oligodeoxynucleotides stimulate innate immune signalling and are of significant interest as therapeutics. Here the authors show that at high doses, these molecules induce an opposite, tolerogenic effect, acting through a previously uncharacterized Toll-like receptor-dependent pathway.
- Claudia Volpi
- , Francesca Fallarino
- & Paolo Puccetti
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| Open AccessMutually exclusive regulation of T cell survival by IL-7R and antigen receptor-induced signals
Before antigen exposure, T cell survival is dependent on signalling stimulated by IL-7. Koenen et al. show that upon encountering specific antigen, T cell receptor signalling initiates a different set of survival pathways, which actively suppress those that sustain naive T cells.
- Paul Koenen
- , Susanne Heinzel
- & Philip D. Hodgkin
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TRPM2 links oxidative stress to NLRP3 inflammasome activation
Activation of the NLRP3 inflammasome by particulate matter such as crystals is known to depend on the generation of reactive oxygen species. Zhong et al. now show that liposomes stimulate the same pathway, and oxidative stress activates NLRP3 by promoting calcium influx through TRPM2 channels.
- Zhenyu Zhong
- , Yougang Zhai
- & Liang Qiao
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Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans
Systemic infection with the fungal pathogenC. albicans is characterized by high mortality, and the precise antifungal defence mechanisms in humans are poorly defined. Using a systems approach, Smeekens et al. describe a previously unknown role for type I interferons in human anti-Candidadefence.
- Sanne P. Smeekens
- , Aylwin Ng
- & Ramnik J. Xavier
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Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.
- Isabel Romero-Camarero
- , Xiaoyu Jiang
- & Izidore S Lossos
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PPARγ is an E3 ligase that induces the degradation of NFκB/p65
NFκB/p65 and PPARγ are both transcription factors that perform distinct but overlapping roles in cellular regulation. Hou et al. report that PPARγ acts as an E3 ubiquitin ligase and promotes Lys48-linked ubiquitination and degradation of p65, terminating NFκB-mediated inflammation and tumorigenesis.
- Yongzhong Hou
- , France Moreau
- & Kris Chadee