Histones trigger sterile inflammation by activating the NLRP3 inflammasome
TLDR
In this paper, the authors identify cytosolic uptake of necrotic cell-derived histones as a triggering mechanism of sterile inflammation, which involves NLRP3 inflammasome activation and IL 1β secretion via oxidative stress.Abstract:
Sterile cell death mediated inflammation is linked to several pathological disorders and involves danger recognition of intracellular molecules released by necrotic cells that activate different groups of innate pattern recognition receptors. Toll-like receptors directly interact with their extrinsic or intrinsic agonists and induce multiple proinflammatory mediators. In contrast, the NLRP3 inflammasome is rather thought to represent a downstream element integrating various indirect stimuli into proteolytic cleavage of interleukin (IL)–1β and IL-18. Here, we report that histones released from necrotic cells induce IL-1β secretion in an NLRP3–ASC-caspase-1-dependent manner. Genetic deletion of NLRP3 in mice significantly attenuated histone-induced IL-1β production and neutrophil recruitment. Furthermore, necrotic cells induced neutrophil recruitment, which was significantly reduced by histone-neutralizing antibodies or depleting extracellular histones via enzymatic degradation. These results identify cytosolic uptake of necrotic cell-derived histones as a triggering mechanism of sterile inflammation, which involves NLRP3 inflammasome activation and IL-1β secretion via oxidative stress.read more
Citations
More filters
Journal ArticleDOI
Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns
TL;DR: In this review, the diverse nature, structural characteristics, and signaling pathways elicited by DAMPs will be critically evaluated.
Journal ArticleDOI
Ligand-Targeted Drug Delivery
TL;DR: Criteria that must be met during design of ligand-targeted drugs (LTDs) to achieve the required therapeutic potency with minimal toxicity are summarized.
Journal ArticleDOI
Release and activity of histone in diseases
TL;DR: Elevated serum histone and nucleosome levels have been implicated in multiple pathophysiological processes and progression of diseases including autoimmune diseases, inflammatory diseases, and cancer and could serve as biomarkers and novel therapeutic targets in human diseases.
Journal ArticleDOI
Extracellular histones in tissue injury and inflammation
TL;DR: Extracellular histones contribute to the microvascular complications of sepsis, major trauma, small vessel vasculitis as well as acute liver, kidney, brain, and lung injury and prevent the degradation of extracellular DNA, which promotesautoimmunization, anti-nuclear antibody formation, and autoimmunity in susceptible individuals.
Journal ArticleDOI
Critical Role for the NLRP3 Inflammasome during Acute Lung Injury
Jamison J. Grailer,Bethany A. Canning,Miriam Kalbitz,Mikel D. Haggadone,Rasika M. Dhond,Anuska V. Andjelkovic,Firas S. Zetoune,Peter A. Ward +7 more
TL;DR: Findings suggest novel targets for treatment of ALI, for which there is currently no known efficacious drug, and an interaction between extracellular histones and the NLRP3 inflammasome, resulting in ALI.
References
More filters
Journal ArticleDOI
Gout-associated uric acid crystals activate the NALP3 inflammasome
TL;DR: It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.
Journal ArticleDOI
A role for mitochondria in NLRP3 inflammasome activation
TL;DR: It is shown that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome, and may explain the frequent association of mitochondrial damage with inflammatory diseases.
Journal ArticleDOI
Circulating mitochondrial DAMPs cause inflammatory responses to injury
Qin Zhang,Mustafa Raoof,Yu Chen,Yuka Sumi,Tolga Sursal,Wolfgang G. Junger,Karim Brohi,Kiyoshi Itagaki,Carl J. Hauser +8 more
TL;DR: It is shown that injury releases mitochondrial DAMPs into the circulation with functionally important immune consequences, including formyl peptides and mitochondrial DNA, which promote PMN Ca2+ flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo.
Journal ArticleDOI
Cryopyrin activates the inflammasome in response to toxins and ATP
Sanjeev Mariathasan,David S. Weiss,Kim Newton,Jacqueline McBride,Karen O'Rourke,Meron Roose-Girma,Wyne P. Lee,Yvette Weinrauch,Denise M. Monack,Vishva M. Dixit +9 more
TL;DR: It is shown that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels.
Journal ArticleDOI
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
Veit Hornung,Franz Bauernfeind,Annett Halle,Eivind O. Samstad,Eivind O. Samstad,Hajime Kono,Kenneth L. Rock,Katherine A. Fitzgerald,Eicke Latz,Eicke Latz +9 more
TL;DR: It is demonstrated that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3, which senses lysosomal damage as an endogenous 'danger' signal.
Related Papers (5)
Histones from Dying Renal Cells Aggravate Kidney Injury via TLR2 and TLR4
Ramanjaneyulu Allam,Christina Rebecca Scherbaum,Murthy N. Darisipudi,Shrikant R. Mulay,Holger Hägele,Julia Lichtnekert,Jan H. Hagemann,Khader Valli Rupanagudi,Mi Ryu,Claudia Schwarzenberger,Bernd Hohenstein,Christian Hugo,Bernd Uhl,Christoph A. Reichel,Fritz Krombach,Marc Monestier,Helen Liapis,Kristin Moreth,Liliana Schaefer,Hans-Joachim Anders +19 more