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| Open AccessCLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation
The NLRP3 inflammasome is key to the regulation of innate immunity against pathogens or stress, but the underlying signaling regulation is still unclear. Here the authors show that chloride intracellular channels (CLIC) interface between mitochondria stress and inflammasome activation to modulate inflammatory responses.
- Tiantian Tang
- , Xueting Lang
- & Rongbin Zhou
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Article
| Open AccessNatural variation of macrophage activation as disease-relevant phenotype predictive of inflammation and cancer survival
The inter-individual variation of the immune system broadly impacts pathophysiology. Here, the authors use the hybrid mouse diversity panel as a surrogate for human natural immune variation and derive a macrophages gene signature robustly correlating with susceptibility to macrophage-related disorders in humans.
- Konrad Buscher
- , Erik Ehinger
- & Klaus Ley
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Article
| Open AccessHypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation
Hypoxia and HIF-1α activation are protective in mouse models of colitis, and the latter regulates autophagy. Here Cosin-Roger et al. show that hypoxia ameliorates intestinal inflammation in Crohn’s patients and murine colitis models by inhibiting mTOR/NLRP3 pathway and promoting autophagy.
- Jesus Cosin-Roger
- , Simona Simmen
- & Pedro A. Ruiz
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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 AccessThe ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation
Caveolae and their major constituent Caveolin-1 (CAV1) play an important role in signalling pathways involved in inflammation, but regulators of CAV1 protein stability are unknown. Here, the authors show that E3 ubiquitin ligase ZNRF1 induces degradation of CAV1 in response to TLR4 activation, and mediates the pro-inflammatory response bothin vitro and in vivo.
- Chih-Yuan Lee
- , Ting-Yu Lai
- & Li-Chung Hsu
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Article
| Open AccessExploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis
Dysfunction of autophagy in plaque macrophages aggravates atherosclerosis. Here the authors show that induction of macrophage autophagy–lysosomal biogenesis either genetically by overexpression of the master transcriptional regulator of this process, TFEB, or pharmacologically with trehalose is atheroprotective.
- Ismail Sergin
- , Trent D. Evans
- & Babak Razani
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Article
| Open AccessThe PYRIN domain-only protein POP2 inhibits inflammasome priming and activation
Excessive inflammasome activation leads to inflammatory diseases, but how inflammasomes are regulated by PYD-only adaptors is unclear. Here the authors show that the PYD-only protein POP2 inhibits both inflammasome priming and assembly by interfering, respectively, with IκBα activation and NLRP3-ASC interaction.
- Rojo A. Ratsimandresy
- , Lan H. Chu
- & Christian Stehlik
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Article
| Open AccessPyrin-only protein 2 limits inflammation but improves protection against bacteria
Pyrin-only proteins (POPs) are primate-specific negative regulators of inflammasome activation. Here the authors generate transgenic mice expressing POP2 under the control of the human promoter, and show that POP2 is important for balancing antibacterial inflammatory responsesin vivo.
- Sivakumar Periasamy
- , Kristen A. Porter
- & Jonathan A. Harton
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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 AccessTGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension
Thrombospondin-1 (TSP-1) activates latent TGF-β in the extracellular matrix. Here the authors show that inappropriate activation of latent TGF-β in murine, bovine and human lung by monocyte-produced TSP-1 causes pulmonary hypertension, and that interference with the activation process prevents disease development.
- Rahul Kumar
- , Claudia Mickael
- & Brian B. Graham
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Article
| Open AccessAntigen-specific CD8+ T cell feedback activates NLRP3 inflammasome in antigen-presenting cells through perforin
Perforin is part of the cytotoxic effector mechanism of CD8+ T cells. Here the authors show that antigen-induced perforin release from CD8 T cells into antigen-presenting cells can activate NLRP3 inflammasome to constitute a positive feedback loop to promote anti-tumour immunity and allo-responses.
- Yikun Yao
- , Siyuan Chen
- & Youcun Qian
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Article
| Open AccessL-selectin mechanochemistry restricts neutrophil priming in vivo
Neutrophil adhesion is tightly regulated to enforce protective immunity, but it is unclear how mechanochemical processes such as catch bonds and slip bonds modulate neutrophilsin vivo. Here the authors show that a point mutation in the adhesion molecule L-selectin alters mechanochemical regulation to affect neutrophil functions in mice.
- Zhenghui Liu
- , Tadayuki Yago
- & Rodger P. McEver
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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 AccessStructure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma
The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.
- Kenneth Verstraete
- , Frank Peelman
- & Savvas N. Savvides
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Article
| Open AccessE3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses
The innate immune response to many RNA viruses depends on recognition of viral RNA by RIG-I. Here the authors show that, upon virus infection, FBXW7 interacts with RIG-I and inhibits ubiquitin-mediated degradation of RIG-I, resulting in increased interferon signallingin vitro and in vivo.
- Yinjing Song
- , Lihua Lai
- & Qingqing Wang
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Article
| Open AccessTopical tacrolimus for the treatment of secondary lymphedema
Secondary lymphedema is a debilitating disease with no cure. Here the authors show that topical application of an FDA-approved anti-T cell drug tacrolimus potently prevents development and alleviates pathologic changes of established lymphedema in mice, suggesting a new treatment for human patients.
- Jason C. Gardenier
- , Raghu P. Kataru
- & Babak J. Mehrara
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Article
| Open AccessTransitional changes in the CRP structure lead to the exposure of proinflammatory binding sites
C-reactive protein is a pentameric protein secreted by the liver in response to injury and infection. Here Braiget al. show that conformational changes in CRP on the surface of monocyte-derived microvesicles enable binding of complement C1q and lead to activation of the complement cascade and aggravation of inflammation.
- David Braig
- , Tracy L. Nero
- & Steffen U. Eisenhardt
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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 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 mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia
Non-resolving bacterial pneumonia results in lung tissue damage owing to overactive inflammation. Here the authors show that the mitochondrial DAMP cardiolipin contributes to persistent inflammation by SUMOylating PPARγ, which promotes binding of the corepressor NCOR/HDAC3 complex to the IL-10 promoter.
- Krishnendu Chakraborty
- , Mahesh Raundhal
- & Prabir Ray
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Article
| Open AccessProphylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
Acute kidney injury can progress to chronic kidney disease. Here Dehnadiet al. develop a post-ischaemic chronic kidney disease model in cynomolgus monkeys and show that prophylactic inhibition of CD11b/CD18 leukocyte receptor via a monoclonal antibody inhibits progression of kidney disease and fibrosis.
- Abbas Dehnadi
- , A. Benedict Cosimi
- & M. Amin Arnaout
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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 AccessMonocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation
Imiquimod exacerbates IL-23-induced skin inflammation and models psoriasis in mice. Here the authors show that this pathology is not dependent on resident dendritic cells, but on CCR6-induced immigration of monocyte-derived cells.
- Tej Pratap Singh
- , Howard H. Zhang
- & Joshua M. Farber
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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 AccessUSP21 prevents the generation of T-helper-1-like Treg cells
The immunosuppressive role of regulatory T (Treg) cells largely depends on their virtue of expressing the transcription factor FOXP3. Here the authors show that the E3 deubiquitinase USP21 stabilizes FOXP3 by mediating its deubiquitination and helps to maintain the expression of Treg signature genes and Treg lineage stability in mice.
- Yangyang Li
- , Yue Lu
- & Bin Li
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Article
| Open AccessHyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes
Patients with diabetes often have delayed wound healing, associated with excessive inflammation. Here the authors report that REG3A inhibits TLR3-driven inflammation in skin wounds, and show that REG3A is reduced in models of diabetes, which exacerbates inflammation in diabetic wounds.
- Yelin Wu
- , Yanchun Quan
- & Yuping Lai
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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
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Article
| Open AccessPKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation
Inflammation involves a Warburg effect that switches cellular metabolism to glycolysis. Here the authors show this switch drives IL-1β, IL-18 and HMGB1 release from macrophages by activating the NLRP3 and AIM2 inflammasomes via protein kinase R phosphorylation, a pathway that can be inhibited to prevent sepsis in mice.
- Min Xie
- , Yan Yu
- & Daolin Tang
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Article
| Open Access25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome
The mechanism underlying neuroinflammation in X-linked adrenoleukodystrophy (ALD) is poorly understood. Here authors identify aberrant production of 25-hydroxycholesterol (25-HC) in ALD patient-derived cells, and show that 25-HC mediates neuroinflammation via activating the NLRP3 inflammasome.
- Jiho Jang
- , Sangjun Park
- & Dong-Wook Kim
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Article
| Open AccessNlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment
The role of NLRP12 in immunity to bacterial infection is controversial as varied and contrasting results have been published using C57BL/6 mice. Here the authors shed light on this issue, showing that unlike C57BL/6N mice, C57BL/6J mice have a missense point mutation in NLRP12 that is associated with defective neutrophil recruitment.
- Tyler K. Ulland
- , Nidhi Jain
- & Fayyaz S. Sutterwala
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Article
| Open AccessEpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance
The intestinal tract is continually exposed to foreign material and gut homeostasis is dependent on tolerance. Here, the authors show that extracellular vesicles released from intestinal epithelial cells stimulate T regulatory cells and immunosuppressive dendritic cells.
- Lingling Jiang
- , Yingying Shen
- & Zhijian Cai
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Article
| Open AccessPalmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome
Breaking down the endothelial barrier is a hallmark of systemic inflammatory response syndrome. Here the authors show that palmitoylation, a post-translational modification of proteins, plays a critical role in altering endothelial function during inflammation, and suggest the targeting of palmitoyl acyltransferase DHHC21 as potential disease therapy.
- Richard S. Beard Jr.
- , Xiaoyuan Yang
- & Sarah Y. Yuan
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Article
| Open AccessFat-associated lymphoid clusters control local IgM secretion during pleural infection and lung inflammation
Fat-associated lymphoid clusters (FALC) in the serous cavities house rapid IgM-producing B1 cells, but how the clusters are activated to respond to infection is unclear. Here the authors show that in response to lung inflammation or pleural nematode infection adipose stromal cell-derived IL-33 activates ILC2s to produce IL-5, thus driving the B1 response in the FALCs.
- Lucy H. Jackson-Jones
- , Sheelagh M. Duncan
- & Cécile Bénézech
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Article
| Open AccessNeutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis
Integrin β2 attachment regulates inflammation via effects on neutrophil rolling and extravasation through sequential integrin extension then headpiece opening. Here the authors show an alternative open headpiece prior to extension stabilized in cisby ICAM-1 that limits neutrophil adhesion.
- Zhichao Fan
- , Sara McArdle
- & Klaus Ley
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Article
| Open AccessFenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models
NSAID-induced analgesia is typically induced by inhibition of COX enzymes. Here the authors show instead that fenamate NSAIDs inhibit the Nlrp3 inflammasome via an effect on volume-regulated anion channel function and also repurpose these drugs for therapeutic effect in rodent models of Alzheimer disease.
- Michael J. D. Daniels
- , Jack Rivers-Auty
- & David Brough
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Article
| Open AccessPhagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution
Hypoxia induced during inflammation promotes the resolution phase. Here the authors show that the hypoxia results from the respiratory burst in myeloid cells, and induces local EPO production and signaling, which enhances macrophage phagocytosis of debris and migration to draining lymph nodes to promote resolution.
- Bangwei Luo
- , Jinsong Wang
- & Zhiren Zhang
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Article
| Open AccessNeutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins
The role of guanylate-binding proteins (GBPs) in innate immunity is increasingly recognized. Here the authors show that GBP4 activates inflammasome in zebrafish neutrophils, and that this process is critical for the clearance of Salmonellainfection via prostaglandin D2.
- Sylwia D. Tyrkalska
- , Sergio Candel
- & Victoriano Mulero
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Article
| Open AccessASC filament formation serves as a signal amplification mechanism for inflammasomes
Inflammasomes regulate IL-1β family maturation and pyroptosis. Here the authors show that ASC oligomerization and the formation of ASC specks are needed for IL-1β processing, but are not required for pyroptosis, indicating distinct inflammasome regulatory pathways.
- Mathias S. Dick
- , Lorenzo Sborgi
- & Petr Broz
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Article
| Open AccessThe necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance
The kinase RIPK3 initiates necroptosis, which has been reported to promote inflammation in various pathological conditions. Here, the authors show that genetic ablation of Ripk3results in adipocyte apoptosis and white adipose tissue inflammation in obese mice, which promotes glucose intolerance.
- Jérémie Gautheron
- , Mihael Vucur
- & Tom Luedde
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Article
| Open AccessRPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA
A central antiviral defence is immune recognition of cystolic DNA. Here the authors show that RPA and RAD51, in cooperation with TREX1, function to protect the cytosol from self-DNA.
- Christine Wolf
- , Alexander Rapp
- & Min Ae Lee-Kirsch
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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 AccessNrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.
- Eri H. Kobayashi
- , Takafumi Suzuki
- & Masayuki Yamamoto
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Article
| Open AccessPseudomonas aeruginosa elastase cleaves a C-terminal peptide from human thrombin that inhibits host inflammatory responses
Neutrophil elastase cleaves thrombin generating anti-inflammatory peptides. Here the authors show that cleavage of thrombin by Pseudomonas aeruginosaelastase generates a peptide that prevents TLR dimerization and signaling, interfering with the inflammatory response to avoid host defense.
- Mariena J. A. van der Plas
- , Ravi K. V. Bhongir
- & Artur Schmidtchen
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Article
| Open AccessMarginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling
Marginal zone B cells are mostly characterized in the context of host defense against bacterial blood-borne pathogens. Here the authors show that TLR4 signaling in these cells requires Fcα/μR (CD351) and that they are a major source of IL-6 in a mouse model of sepsis.
- Shin-ichiro Honda
- , Kazuki Sato
- & Akira Shibuya
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| Open AccessThe obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation
Visceral and subcutaneous fat are associated with different metabolic risk, but mediators of such depot specific effects are not very well known. Here the authors identify the transcriptional regulator, TRIP-Br2, as a regulator of endoplasmic reticulum (ER) stress-induced inflammatory responses specifically in visceral fat.
- Guifen Qiang
- , Hyerim Whang Kong
- & Chong Wee Liew
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Article
| Open AccessMincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution
Resolution of granulomas in mycobacterial infection requires macrophages to switch from cytokine to nitric oxide (NO) production. Here the authors show that Mincle stimulates translation of the key NO synthesis genes by a mechanism dependent on p38-mediated hypusination of eiF5A.
- Wook-Bin Lee
- , Ji-Seon Kang
- & Young-Joon Kim