The role of extracellular histone in organ injury

Silk, Eleanor; Zhao, Hailin; Weng, Hao; Ma, Ding

doi:10.1038/cddis.2017.52

Cited by 241 publications

(221 citation statements)

References 109 publications

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“…However, it remains difficult to determine whether this is the case as there is a lack of antibodies that can clearly distinguish between the two histone forms. 41,42 Although in our study we did not directly address the role of histones, using TLR reporter lines we demonstrated that NET fragments elicited potent TLR2 and -4 activation that could be mostly extinguished by complete digestion of NETs. We also observed that NET fragments stimulated TLR9 activation.…”

Section: Discussionmentioning

confidence: 70%

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

Scozzi

Wang

Liao

et al. 2019

American Journal of Transplantation

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Neutrophil extracellular traps (NETs) have been shown to worsen acute pulmonary injury including after lung transplantation. The breakdown of NETs by DNAse‐1 can help restore lung function, but whether there is an impact on allograft tolerance remains less clear. Using intravital 2‐photon microscopy, we analyzed the effects of DNAse‐1 on NETs in mouse orthotopic lung allografts damaged by ischemia‐reperfusion injury. Although DNAse‐1 treatment rapidly degrades intragraft NETs, the consequential release of NET fragments induces prolonged interactions between infiltrating CD4+ T cells and donor‐derived antigen presenting cells. DNAse‐1 generated NET fragments also promote human alveolar macrophage inflammatory cytokine production and prime dendritic cells for alloantigen‐specific CD4+ T cell proliferation through activating toll‐like receptor (TLR) — Myeloid Differentiation Primary Response 88 (MyD88) signaling pathways. Furthermore, and in contrast to allograft recipients with a deficiency in NET generation due to a neutrophil‐specific ablation of Protein Arginine Deiminase 4 (PAD4), DNAse‐1 administration to wild‐type recipients promotes the recognition of allo‐ and self‐antigens and prevents immunosuppression‐mediated lung allograft acceptance through a MyD88‐dependent pathway. Taken together, these data show that the rapid catalytic release of NET fragments promotes innate immune responses that prevent lung transplant tolerance.

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Section: Discussionmentioning

confidence: 70%

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

Scozzi

Wang

Liao

et al. 2019

American Journal of Transplantation

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“…Release of nucleosomes is considered to reflect cell death . Elevated circulating levels of nucleosomes have been detected in several conditions, including trauma, ischemia–reperfusion injury, and sepsis .…”

Section: Discussionmentioning

confidence: 99%

“…Because of this limitation, subjects received ASCs prior to LPS, whereas posttreatment would better resemble the clinical scenario. Release of nucleosomes is considered to reflect cell death [78,79]. Elevated circulating levels of nucleosomes have been detected in several conditions, including trauma, ischemiareperfusion injury, and sepsis [49,50,78,79].…”

Section: Discussionmentioning

confidence: 99%

Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial

et al. 2018

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In experimental models, mesenchymal stem cells (MSCs) can modulate various immune responses implicated in the pathogenesis of sepsis. Intravenous injection of lipopolysaccharide (LPS) into healthy subjects represents a model with relevance for the host response to sepsis. To explore the use of MSCs in sepsis, we determined their effect on the response to intravenous LPS in a randomized study in 32 healthy subjects with four treatment arms: placebo or allogeneic adipose MSCs (ASCs) intravenously at either 0.25 × 10 , 1 × 10 , or 4 × 10 cells/kg; all subjects received LPS intravenously (2 ng/kg) one hour after the end of ASC infusion (Trial Register number 2014-002537-63, clinicaltrials.gov identifier NCT02328612). Infusion of ASCs was well tolerated. The high ASC dose increased the febrile response, exerted mixed pro-inflammatory (enhanced interleukin-8 and nucleosome release) and anti-inflammatory effects (increased interleukin-10 and transforming growth factor-β release), and enhanced coagulation activation and reduced the fibrinolytic response. Blood leukocyte transcriptome analyses showed a biphasic effect of ASCs on the LPS response: at 2 hours post LPS, ASC-infused subjects displayed higher expression of genes involved in innate immune pathways, whereas at 4 hours post LPS these subjects had lower expression of innate immune pathway genes. Infusion of ASCs did not modify the "ex vivo" responsiveness of whole blood to various bacterial agonists. These results indicate that intravenous infusion of allogeneic ASCs (4 × 10 cells/kg) has a variety of proinflammatory, anti-inflammatory, and procoagulant effects during human endotoxemia. Further studies are needed to assess the safety and efficacy of ASCs in sepsis patients. Stem Cells 2018;36:1778-1788.

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“…In this same work, it was verified that this antimicrobial response was due to the protein content of this organelle, mainly due to the action of histones. 32 Despite being a cationic protein canonically involved in the formation and maintenance of nucleosomes, 130 histones are cytotoxic in vitro and in vivo when located in the extracellular environment, or when in excess in the cytoplasm, furthermore, they have a strong ability to kill bacteria [130][131][132] (Fig. 1).…”

Section: Ld Functions In Bacterial Infectionmentioning

confidence: 99%

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

Pereira-Dutra

Teixeira

Costa

et al. 2019

Journal of Leukocyte Biology

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Increased accumulation of cytoplasmic lipid droplets (LDs) in host nonadipose cells is commonly observed in response to numerous infectious diseases, including bacterial, parasite, and fungal infections. LDs are lipid‐enriched, dynamic organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell and stimulus regulated. Far beyond being simply a deposit of neutral lipids, LDs have come to be seen as an essential platform for various cellular processes, including metabolic regulation, cell signaling, and the immune response. LD participation in the immune response occurs as sites for compartmentalization of several immunometabolic signaling pathways, production of inflammatory lipid mediators, and regulation of antigen presentation. Infection‐driven LD biogenesis is a complexly regulated process that involves innate immune receptors, transcriptional and posttranscriptional regulation, increased lipid uptake, and new lipid synthesis. Accumulating evidence demonstrates that intracellular pathogens are able to exploit LDs as an energy source, a replication site, and/or a mechanism of immune response evasion. Nevertheless, LDs can also act in favor of the host as part of the immune and inflammatory response to pathogens. Here, we review recent findings that explored the new roles of LDs in the context of host‐pathogen interactions.

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The role of extracellular histone in organ injury

Cited by 241 publications

References 109 publications

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

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