Featured
-
-
Article
| Open AccessTargeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs
In this work, the authors report a drug class based on an ancient innate defense fold. Inspired by Nature’s anti-infective strategies, this peptide-based drug targets systemic inflammation via multiple molecular interactions, enhancing effectiveness
- Ganna Petruk
- , Manoj Puthia
- & Artur Schmidtchen
-
Article
| Open AccessDimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon
Infectious disease associated with excessive inflammation can result in coagulopathy. Here the authors show use of the clinically approved therapy dimethyl fumarate, as well as the pre-clinical tool compound 4- octyl itaconate, modulate tissue factor related coagulopathy via inhibition of the myeloid type I interferon pathway-tissue factor axis.
- Tristram A. J. Ryan
- , Alexander Hooftman
- & Luke A. J. O’Neill
-
Article
| Open AccessMicrobe capture by splenic macrophages triggers sepsis via T cell-death-dependent neutrophil lifespan shortening
Hyperinflammation and immune dysfunction are key drivers of immunopathology in sepsis. Here the authors show microbial exploitation of phagocytic receptors is linked to triggering of sepsis and the immune cell mediated reduction in neutrophil life span.
- Marianna Ioannou
- , Dennis Hoving
- & Venizelos Papayannopoulos
-
Article
| Open AccessNeutrophils restrain sepsis associated coagulopathy via extracellular vesicles carrying superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis
Disseminated intravascular coagulation is associated with sepsis and a number of inflammatory components have been linked to sepsis associated coagulopathy. Here the authors show neutrophils can prevent lethal coagulopathy via the production of extracellular vesicles that carry superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis.
- Wenjie Bao
- , Huayue Xing
- & Xiaolong Liu
-
Article
| Open AccessKir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters
Potassium channels and membrane potential may influence macrophage function during inflammation. Here the authors show that the Kir2.1 potassium channel affects macrophage metabolism by altering cell surface retention of nutrient transporters and subsequently regulates inflammatory disease responses.
- Weiwei Yu
- , Zhen Wang
- & Di Wang
-
Article
| Open AccessSynthetic hydrogel nanoparticles for sepsis therapy
Sepsis caused by the release of inflammatory mediators into the blood is a life threatening disease. Here, the authors report on the development of hydrogel nanoparticles for the capture and neutralisation of histones, major inflammatory mediators, and demonstrate sepsis treatment in a murine model.
- Hiroyuki Koide
- , Anna Okishima
- & Kenneth J. Shea
-
Article
| Open AccessTargeting Gα13-integrin interaction ameliorates systemic inflammation
Bacterial or viral infection can lead to lethal systemic inflammation and thrombosis. Here, the authors show that inhibiting integrin outside-in signaling in leukocytes and platelets alleviates inflammation/clotting and improved survival in septic mice.
- Ni Cheng
- , Yaping Zhang
- & Xiaoping Du
-
Article
| Open AccessFeeding-induced resistance to acute lethal sepsis is dependent on hepatic BMAL1 and FXR signalling
Time of day influences immune responses and lethality in response to LPS, with survival greatest at the beginning compared to the end of the light cycle. Here the authors show that feeding, rather than light, controls time-of-day dependent LPS sensitivity through the liver clock and hepatic FXR signalling.
- Sarah S. Geiger
- , Javier Traba
- & Richard M. Siegel
-
Article
| Open AccessUltra-sensitive and rapid detection of nucleic acids and microorganisms in body fluids using single-molecule tethering
Culture-based diagnostic methods for microorganism detection are time-consuming but still the gold standard for conditions such as sepsis. Here the authors present an amplification and purification-free method to detect microorganisms in bodily fluids with high sensitivity: Single MOLecule Tethering (SMOLT).
- Wen-Chih Cheng
- , Troy Horn
- & Alfredo Celedon
-
Article
| Open AccessUltrasensitive digital quantification of cytokines and bacteria predicts septic shock outcomes
Ultrasensitive methods for detection of biomarkers for infectious disease are needed for diagnosing, monitoring and targeting treatment. Here the authors develop a digital assay for inflammatory markers, bacterial DNA and antibotic-resistance genes and apply it to characterise asthma patients and predict mortality from septic shock.
- M. Fatih Abasıyanık
- , Krysta Wolfe
- & Savaş Tay
-
Article
| Open AccessFecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity
Sepsis due to multidrug resistant pathogens is the most common cause of death in intensive care units. Here, the authors report that fecal microbiota transplant (FMT) can rescue mice from lethal sepsis of pathogens isolated from stool of a critically ill patient and show that FMT reverses the immunosuppressive effect induced by the pathogen community.
- Sangman M. Kim
- , Jennifer R. DeFazio
- & John C. Alverdy
-
Article
| Open AccessExtracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation
The enzyme nicotinate phosphoribosyltransferase (NAPRT) mediates the rate-limiting step in NAD salvage pathway starting from nicotinic acid. Here the authors show that NAPRT can be detected extracellularly, binds to Toll like receptor 4, and activates NF-kB signaling and cytokine production in macrophage via NAD synthesis-independent pathways.
- Antonella Managò
- , Valentina Audrito
- & Silvia Deaglio
-
Article
| Open AccessSox17 is required for endothelial regeneration following inflammation-induced vascular injury
Endothelial cell regeneration is essential for blood vessels to recover from inflammation-induced injury. Here Liu et al. show that the transcription factor Sox17 is required for endothelial regeneration following endotoxemia, and that delivery of a transgene expressing Sox17 to lung endothelial cells enhances recovery after injury.
- Menglin Liu
- , Lianghui Zhang
- & Asrar B. Malik
-
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
-
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
-
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
-
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
-
Article
| Open AccessNMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury
Damage-associated molecular patterns (DAMP) are important mediators of innate immunity. Here the authors show that N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs to promote inflammation by activating macrophages via the Toll-like receptor 4 and NF-κB pathways.
- Zhikai Xiahou
- , Xiangli Wang
- & Huanhuan Liang
-
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
-
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
-
Article
| Open AccessProtection from septic peritonitis by rapid neutrophil recruitment through omental high endothelial venules
Neutrophils are critical in preventing the transition of acute peritoneal infection to sepsis. Here the authors show in three mouse models of peritonitis that neutrophils enter the abdominal cavity via high endothelial venules of the greater omentum, and characterize adhesion molecules involved.
- Konrad Buscher
- , Huiyu Wang
- & Jian Song
-
Article
| Open AccessLarge-scale inference of protein tissue origin in gram-positive sepsis plasma using quantitative targeted proteomics
Sepsis can lead to multiple organ failure that could potentially be reflected by change in plasma protein abundance. Here the authors describe a proteomics strategy that allows the determination of plasma proteins tissue origin in a quantitative manner for use as biomarkers—illustrated in a mouse model of sepsis.
- Erik Malmström
- , Ola Kilsgård
- & Johan Malmström
-
Article
| Open AccessSepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy
Sepsis patients often develop muscle atrophy that can last for years. Here the authors show in a mouse model that sepsis causes long-term impairment of the satellite cells, affecting mitochondrial function and energy metabolism, and that injection of mesenchymal stem cells restores satellite cell metabolism and muscle regeneration.
- P. Rocheteau
- , L. Chatre
- & F. Chrétien
-
Article |
Oestrogen sulfotransferase ablation sensitizes mice to sepsis
Sepsis, a systemic inflammatory response to bacterial infection, can lead to organ failure and death. Here, Chai et al.investigate the mechanisms behind the septic response and identify the role of oestrogen sulfotransferase in this process in mice.
- Xiaojuan Chai
- , Yan Guo
- & Wen Xie
-
Article
| Open AccessRapid detection of single bacteria in unprocessed blood using Integrated Comprehensive Droplet Digital Detection
Early detection of blood stream infections is essential for providing effective treatments. Here the authors present a system integrating DNAzyme sensors, droplet microfluidics and a high-throughput 3D particle counter that can detect specific, single bacterial cells in blood within a few hours.
- Dong-Ku Kang
- , M. Monsur Ali
- & Weian Zhao
-
Article |
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis
The role of metabolic reprogramming in the regulation of innate inflammatory response remains incompletely understood. Here, the authors show that pyruvate kinase M2-mediated aerobic glycolysis contributes to inflammatory response, and that inhibition of this pathway protects mice from lethal endotoxemia and sepsis.
- Liangchun Yang
- , Min Xie
- & Daolin Tang
-
Article |
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