Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury

Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests that it also plays a role in inflam...

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Bibliographic Details
Published in:The Journal of immunology (1950) Vol. 191; no. 5; p. 2665
Main Authors: Huang, Hai, Chen, Hui-Wei, Evankovich, John, Yan, Wei, Rosborough, Brian R, Nace, Gary W, Ding, Qing, Loughran, Patricia, Beer-Stolz, Donna, Billiar, Timothy R, Esmon, Charles T, Tsung, Allan
Format: Journal Article
Language:English
Published: United States 01.09.2013
Subjects:
Animals
Blotting, Western
Carrier Proteins - immunology
Carrier Proteins - metabolism
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Fluorescent Antibody Technique
Histones - immunology
Histones - metabolism
Immunity, Innate - immunology
Inflammasomes - immunology
Inflammasomes - metabolism
Kupffer Cells - immunology
Kupffer Cells - metabolism
Liver - immunology
Liver - injuries
Liver - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
NLR Family, Pyrin Domain-Containing 3 Protein
Real-Time Polymerase Chain Reaction
Reperfusion Injury - immunology
Reverse Transcriptase Polymerase Chain Reaction
ISSN:1550-6606, 1550-6606
Online Access:Get more information
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Summary:Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests that it also plays a role in inflammation driven by endogenous danger-associate molecular pattern molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. In this article, we report that both NLRP3 and its downstream target caspase-1 are activated during I/R and are essential for hepatic I/R injury, because both NLRP3 and caspase-1 knockout mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on caspase-1 expression in liver nonparenchymal cells. Although upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through TLR9. This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and the activation of innate immunity during sterile inflammation.
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ISSN:1550-6606
1550-6606
DOI:10.4049/jimmunol.1202733