title: Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury.
abstract: 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.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Hui-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Evankovich
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.forename: Gary W
authors.initials: GW
authors.lastname: Nace
authors.forename: Qing
authors.initials: Q
authors.lastname: Ding
authors.forename: Patricia
authors.initials: P
authors.lastname: Loughran
authors.forename: Donna
authors.initials: D
authors.lastname: Beer-Stolz
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D006657:Histones; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse
references.citation: J Clin Invest. 2009 Dec;119(12):3502-11
references.pmid: 19955661
references.citation: J Immunol. 2011 Nov 1;187(9):4809-17
references.pmid: 21940680
references.citation: Nitric Oxide. 2013 May 31;31:9-19
references.pmid: 23474170
references.citation: J Immunol. 2010 Nov 15;185(10):6277-85
references.pmid: 20962258
references.citation: Annu Rev Immunol. 2011;29:707-35
references.pmid: 21219188
references.citation: Crit Care Med. 2003 Jul;31(7):1947-51
references.pmid: 12847387
references.citation: Mol Med. 2008 May-Jun;14(5-6):337-45
references.pmid: 18292799
references.citation: J Exp Med. 2007 Nov 26;204(12):2913-23
references.pmid: 17984303
references.citation: PLoS One. 2011;6(6):e20398
references.pmid: 21687712
references.citation: Lupus. 2008 May;17(5):431-6
references.pmid: 18490422
references.citation: Immunol Rev. 2011 Sep;243(1):136-51
references.pmid: 21884173
references.citation: Nat Med. 2011 Nov 07;17(11):1391-401
references.pmid: 22064429
references.citation: Nature. 2012 Jan 18;481(7381):278-86
references.pmid: 22258606
references.citation: Am J Transplant. 2011 Aug;11(8):1563-9
references.pmid: 21668640
references.citation: J Am Soc Nephrol. 2012 Aug;23(8):1375-88
references.pmid: 22677551
references.citation: Mol Med. 2011 Sep-Oct;17(9-10):1031-8
references.pmid: 21666957
references.citation: Nature. 2006 Mar 9;440(7081):237-41
references.pmid: 16407889
references.citation: Am J Physiol. 1991 Mar;260(3 Pt 1):G355-62
references.pmid: 2003603
references.citation: Nat Immunol. 2011 Mar;12(3):222-30
references.pmid: 21151103
references.citation: Biochem Pharmacol. 2001 Sep 15;62(6):705-12
references.pmid: 11551515
references.citation: J Immunol. 2011 Sep 1;187(5):2626-31
references.pmid: 21784973
references.citation: Gastroenterology. 2011 Jul;141(1):358-69
references.pmid: 21439959
references.citation: Nature. 2006 Mar 9;440(7081):228-32
references.pmid: 16407890
references.citation: Hepatology. 2012 Jun;55(6):1863-75
references.pmid: 22234969
references.citation: Hum Gene Ther. 2011 Jul;22(7):853-64
references.pmid: 21128730
references.citation: Surg Clin North Am. 2010 Aug;90(4):665-77
references.pmid: 20637940
references.citation: J Clin Invest. 2009 Feb;119(2):305-14
references.pmid: 19164858
references.citation: Am J Transplant. 2011 Nov;11(11):2342-52
references.pmid: 21831159
references.citation: Nature. 2010 Apr 29;464(7293):1357-61
references.pmid: 20428172
references.citation: Shock. 2009 Jul;32(1):4-16
references.pmid: 19008778
references.citation: Nat Rev Immunol. 2010 Mar;10(3):210-5
references.pmid: 20168318
references.citation: Gastroenterol Res Pract. 2010;2010:
references.pmid: 20811615
references.citation: Science. 2010 Oct 15;330(6002):362-6
references.pmid: 20947763
references.citation: J Biol Chem. 2010 Dec 17;285(51):39888-97
references.pmid: 20937823
references.citation: Circulation. 2011 Feb 15;123(6):594-604
references.pmid: 21282498
references.citation: Liver Transpl. 2005 Jun;11(6):669-78
references.pmid: 15915489
references.citation: Immunol Rev. 2011 Sep;243(1):152-62
references.pmid: 21884174
references.citation: Hepatology. 2011 Sep 2;54(3):999-1008
references.pmid: 21721026
references.citation: J Clin Invest. 2010 Feb;120(2):559-69
references.pmid: 20093775
references.citation: J Immunol. 2005 Dec 1;175(11):7661-8
references.pmid: 16301676
references.citation: J Inflamm (Lond). 2012 Nov 28;9(1):49
references.pmid: 23192004
references.citation: Proteomics. 2010 Apr;10(7):1484-93
references.pmid: 20127695
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1261-8
references.pmid: 16410367
references.citation: Nat Med. 2009 Nov;15(11):1318-21
references.pmid: 19855397
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20388-93
references.pmid: 19918053
references.citation: Blood. 2011 Aug 18;118(7):1952-61
references.pmid: 21673343
references.citation: Nature. 2011 Jan 13;469(7329):221-5
references.pmid: 21124315
references.citation: J Exp Med. 2005 Apr 4;201(7):1135-43
references.pmid: 15795240