Featured
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| Open AccessREV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis
REV-ERBα is a nuclear receptor that links the circadian pathways with those of metabolism. Here the authors show REV-ERBα is also involved with linking the circadian system with the inflammatory pathways of an experimental model of colitis through regulation of the NF-κB/NLRP3 axis.
- Shuai Wang
- , Yanke Lin
- & Baojian Wu
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Article
| Open AccessPOH1 deubiquitinates pro-interleukin-1β and restricts inflammasome activity
The inflammasomes are important for activating the pro-inflammatory cytokine interleukin-β (IL-1β) for protection against pathogens. Here the authors show that a deubiquitinase, POH1, reduces the conversion of pro-IL-1β into its active form, with in vivo data further implicating a role of POH1 for maintaining immune homeostasis.
- Li Zhang
- , Yun Liu
- & Yongzhong Liu
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Article
| Open AccessComplement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism
Complement, while serving to remove pathogens in the circulation, is also important for synergizing with inflammasomes to modulate CD4 T cell activation. Here the authors show that CD46, a complement receptor expressed only in humans, is essential for inducing optimal activation and effector functions of human CD8 T cells.
- Giuseppina Arbore
- , Erin E. West
- & Claudia Kemper
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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 AccessNLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease
The inflammasome is normally activated by pathogens to induce tissue inflammation. Here the authors show that, in mouse experimental colitis models, Nlrp1 inflammasome sensor activates IL-18 to reduce beneficial colonic Clostridiales species, thereby decreasing microbial butyrate and its protective effects on colitis.
- Hazel Tye
- , Chien-Hsiung Yu
- & Seth L. Masters
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Article
| Open AccessTRIM27 mediates STAT3 activation at retromer-positive structures to promote colitis and colitis-associated carcinogenesis
Aberrant and persistent activation of the transcription factor STAT3 has been found in various types of cancers. Here the authors identify TRIM27 as a positive regulator of IL-6-induced STAT3 activation through the formation of JAK1-STAT3 complex, thus impacting inflammation-induced colon cancer development.
- Hong-Xia Zhang
- , Zhi-Sheng Xu
- & Yan-Yi Wang
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Review Article
| Open AccessResolution of chronic inflammatory disease: universal and tissue-specific concepts
Inflammation is a component of many chronic inflammatory diseases and yet it is understudied in medicine. Here, the authors review novel insights in to inflammation and how impairment of its resolution can lead to diseases.
- Georg Schett
- & Markus F. Neurath
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Article
| Open AccessChromatin regulates IL-33 release and extracellular cytokine activity
Interleukin-33 (IL-33) can be released as a cytokine or transported into the nucleus, but the significance of this nuclear shuttling is not fully understood. Here the authors show that chromatin-binding of IL-33 alters, unexpectedly, the activity of IL-33 both in alarmin release kinetics and receptor signaling capacity.
- Jared Travers
- , Mark Rochman
- & Marc E. Rothenberg
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Article
| Open AccessSensing of cytosolic LPS through caspy2 pyrin domain mediates noncanonical inflammasome activation in zebrafish
In humans, caspase-5 is an LPS sensor that can induce gasdermin D cleavage and pyroptosis. Here, the authors show that zebrafish caspy2 is a functional homolog as it also senses cytosolic LPS to activate the noncanonical inflammasome and to protect against bacterial infection, but it does so via pyrin death domain interactions.
- Dahai Yang
- , Xin Zheng
- & Qin Liu
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Article
| Open AccessSUMO-mediated regulation of NLRP3 modulates inflammasome activity
The NLRP3 inflammasome is an important component of inflammatory responses, but how it is negatively regulated is still unclear. Here the authors show that post-translational modification of NLRP3 by sumoylation suppresses inflammasome activity, and that desumoylation of NLRP3 by the SENP6 and SENP7 proteases promotes NLRP3 activation.
- Rachael Barry
- , Sidonie Wicky John
- & Pascal Meier
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Article
| Open AccessStructural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides
Thrombin-derived C-terminal peptides (TCPs) have anti-endotoxic functions in wounds by binding to bacterial lipopolysaccharide (LPS) and Gram-negative bacteria. Here authors use a spectrum of biophysical techniques to determine the conformation of a TCP in complex with LPS and define the interaction between TCPs and CD14.
- Rathi Saravanan
- , Daniel A Holdbrook
- & Artur Schmidtchen
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Article
| Open AccessIntermedin protects against sepsis by concurrently re-establishing the endothelial barrier and alleviating inflammatory responses
Sepsis is a life-threatening condition. Here, the authors show that intermedin alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. Patients with high intermedin levels exhibit a low risk of shock, lower severity scores, and greatly improved survival outcomes.
- Fei Xiao
- , Denian Wang
- & Wei Zhang
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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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Correspondence
| Open AccessEvidence that neutrophils do not promote Echis carinatus venom-induced tissue destruction
- Julien Stackowicz
- , Bianca Balbino
- & Laurent L. Reber
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Correspondence
| Open AccessReply to ‘Evidence that neutrophils do not promote Echis carinatus venom-induced tissue destruction’
- Kempaiah Kemparaju
- , Kesturu S. Girish
- & Gajanan D. Katkar
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Article
| Open AccessMacrophage migration inhibitory factor is required for NLRP3 inflammasome activation
MIF is a cytokine best known for its modulatory effect on expression of proinflammatory cytokines. Here the authors show that MIF facilitates the NLRP3–vimentin interaction, resulting in Nlrp3 inflammasome activation.
- Tali Lang
- , Jacinta P. W. Lee
- & James Harris
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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 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 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 AccessThe E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome
The NLRP3 inflammasome is important for inducing IL-1β and IL-18 inflammatory responses. Here the authors show, by generating and characterizing Peli2 deficient mice and immune cells, that an E3 ubiquitin ligase Pellino2 promotes inflammasome priming by inducing NLRP3 ubiquitination and by targeting IRAK1.
- Fiachra Humphries
- , Ronan Bergin
- & Paul N. Moynagh
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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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Article
| 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 AccessThe oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages
Non-canonical inflammasome activation is mediated by caspase-11 in mice and caspase-4 in humans. Here the authors show that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) competes with LPS for binding to these caspases and in so doing is a negative regulator of non-canonical inflammasome activation in macrophages, but not in dendritic cells.
- Lan H. Chu
- , Mohanalaxmi Indramohan
- & Christian Stehlik
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Article
| Open AccessDirect conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue
At the site of injury, macrophages exit their characteristic phenotype undergoing direct conversion to fibroblasts. Keratinocyte-derived miR-21, packaged in extracellular vesicles, enables such plasticity which accounts for the vast majority of all fibroblasts in the granulation tissue.
- Mithun Sinha
- , Chandan K. Sen
- & Sashwati Roy
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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 AccessA ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice.
- Dennis Wolf
- , Nathaly Anto-Michel
- & Andreas Zirlik
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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 AccessHuman caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11
Lipid A from some bacteria is sensed differently by humans and mice for the activation of the inflammasomes and inflammatory responses, but the mechanisms are not clear. Here, the authors show that murine caspase-11 and human caspase-4/5 contribute to this differential response via their distinct recognition of under-acylated lipid A.
- Brice Lagrange
- , Sacha Benaoudia
- & Thomas Henry
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Article
| Open AccessZika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1β secretion
The NLRP3 inflammasome plays an important role in antiviral host responses. Here, the authors reveal that the polymerase of Zika virus binds NLRP3 to facilitate inflammasome complex assembly and induce production of IL-1β in human macrophages, human PBMCs and mice, resulting in pathogenesis in mice.
- Wenbiao Wang
- , Geng Li
- & Jianguo Wu
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Article
| Open AccessHuman macrophages differentially produce specific resolvin or leukotriene signals that depend on bacterial pathogenicity
M1 and M2 cells are representative of proinflammatory versus resolving macrophages, respectively. Here the authors characterize the lipid mediator response to bacterial infection by these cells and show that differing panels of leukotrienes and specialized pro-resolving mediators contribute to control of the dichotomy.
- Oliver Werz
- , Jana Gerstmeier
- & Charles N. Serhan
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Article
| Open AccessThe podoplanin-CLEC-2 axis inhibits inflammation in sepsis
Sepsis is a life-threatening condition where exaggerated inflammatory responses lead to severe tissue damage. Here, Rayes and colleagues show that the interaction between podoplanin and its receptor CLEC-2 on platelets plays a critical role in limiting inflammation during sepsis.
- Julie Rayes
- , Siân Lax
- & Steve P. Watson
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Article
| Open AccessNAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease
Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent inflammasome activation in neutrophils contributes to systemic inflammation.
- Randilea D. Nichols
- , Jakob von Moltke
- & Russell E. Vance
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Article
| Open AccessANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ
NF-κB activation mediated by TNFα has a critical role in inflammation; however, the underlying mechanisms await further investigation. Here the authors show that selective autophagy regulates NF-κB activation via an ANGPTL8/p62-IKKγ signaling axis.
- Yu Zhang
- , Xian Guo
- & Kun Huang
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Article
| Open AccessTyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis
The NLRP3 inflammasome is central to a variety of inflammatory diseases, but how it is regulated to prevent excessive inflammation is not clear. Here the authors show that NLRP3 activation causes SHP2 translocation to the mitochondria to interact with and dephosphorylate ANT1, thus stabilizing the mitochondria and preventing release of proinflammatory mitochondrial DNA and ROS.
- Wenjie Guo
- , Wen Liu
- & Qiang Xu
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Article
| Open AccessThe LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation
Excessive inflammation can be tissue destructive and contributes to auotinflammatory diseases and sepsis pathology. Here the authors show that the lncRNA Mirt2 is an endogenous negative feedback regulator of LPS-induced inflammation by limiting ubiquitination of TRAF6 and NF-κB activation.
- Meng Du
- , Lin Yuan
- & Kai Huang
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Article
| Open AccessRemodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis
Inflammasomes are involved in gut homeostasis and inflammatory pathologies. The authors show that a hyperactive NLRP3 inflammasome maintains gut homeostasis through remodelling of the gut microbiota and induction of regulatory T cells.
- Xiaomin Yao
- , Chenhong Zhang
- & Guangxun Meng
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Article
| Open AccessSynergistic gene expression during the acute phase response is characterized by transcription factor assisted loading
The cytokines IL-1β and IL-6 mediate the systemic acute phase response (APR). Here, the authors provide evidence that these cytokines lead to both synergistic and antagonistic gene expression during APR; synergistic induction occurs by assisted loading of STAT3 on chromatin by NF-κB.
- Ido Goldstein
- , Ville Paakinaho
- & Gordon L. Hager
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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 AccessMitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability
Macrophage metabolism controls differentiation and subsequent adaptive immune responses. Here the authors show that mitochondrial membrane protein Fam73b regulates TLR-mediated mitochondrial switching of fusion to fission to induce IL-12 production via accumulation of Parkin and stabilization of IRF1 in macrophages, resulting in control of anti-tumor immunity in mice.
- Zhengjun Gao
- , Yiyuan Li
- & Jin Jin
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Article
| Open AccessGlucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages
Glucocorticoid reduces inflammation by both inducing anti-inflammatory genes and suppressing pro-inflammatory genes, but how these two functions are dictated is unclear. Here the authors show that phosphorylated glucocorticoid receptor-interacting protein 1 (GRIP1) serves as a coactivator for this response in macrophage.
- David A. Rollins
- , Joubert B. Kharlyngdoh
- & Inez Rogatsky
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Article
| Open AccessWiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells
Wiskott-Aldrich syndrome protein (WASp) is essential for controlling the cytoskeleton, but its function in innate immunity is unclear. Here the authors show that WASp deficiency is associated with dysregulated septin cage formation, excessive inflammasome activation, elevated immune cell death and reduced bacterial clearance.
- Pamela P. Lee
- , Damián Lobato-Márquez
- & Adrian J. Thrasher
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Article
| Open AccessMapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers
Although detection of pathogens by pattern recognition receptors is increasingly well defined, recognition of endogenous triggers remains poorly understood. By examining the interface between tenascin-C and TLR4, the authors identify a molecular code that identifies endogenous proteins as inflammatory stimuli.
- Lorena Zuliani-Alvarez
- , Anna M. Marzeda
- & Kim S. Midwood
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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