Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll‐like receptor 9 in mice

Sterile inflammatory insults are known to activate innate immunity and propagate organ damage through the recognition of extracellular damage‐associated molecular pattern (DAMP) molecules. Although DAMPs such as endogenous DNA and nuclear high‐mobility group box 1 have been shown to be critical in s...

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Published in:	Hepatology (Baltimore, Md.) Vol. 54; no. 3; pp. 999 - 1008
Main Authors:	Huang, Hai, Evankovich, John, Yan, Wei, Nace, Gary, Zhang, Lemeng, Ross, Mark, Liao, Xinghua, Billiar, Timothy, Xu, Jun, Esmon, Charles T., Tsung, Allan
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 02.09.2011 Wiley Wolters Kluwer Health, Inc
Subjects:	Animals Biological and medical sciences Cells, Cultured Gastroenterology. Liver. Pancreas. Abdomen Hepatology Histones - physiology HMGB1 Protein - physiology Immunity, Innate Inflammation Inflammation - etiology Liver - blood supply Liver Injury/Regeneration Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Mice Mice, Inbred C57BL Myeloid Differentiation Factor 88 - physiology Reperfusion Injury - prevention & control Rodents Signal Transduction Toll-Like Receptor 9 - physiology Vertebrata Mammalia Mouse Animal Liver Rodentia Gastroenterology Toll like receptor
ISSN:	0270-9139, 1527-3350, 1527-3350
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Summary:	Sterile inflammatory insults are known to activate innate immunity and propagate organ damage through the recognition of extracellular damage‐associated molecular pattern (DAMP) molecules. Although DAMPs such as endogenous DNA and nuclear high‐mobility group box 1 have been shown to be critical in sterile inflammation, the role of nuclear histone proteins has not yet been investigated. We report that endogenous histones function as DAMPs after ischemic injury through the pattern recognition receptor Toll‐like receptor (TLR) 9 to initiate inflammation. Using an in vivo model of hepatic ischemia/reperfusion (I/R) injury, we show that levels of circulating histones are significantly higher after I/R, and that histone neutralization significantly protects against injury. Injection of exogenous histones exacerbates I/R injury through cytotoxic effects mediated by TLR9 and MyD88. In addition, histone administration increases TLR9 activation, whereas neither TLR9 nor MyD88 mutant mice respond to exogenous histones. Furthermore, we demonstrate in vitro that extracellular histones enhance DNA‐mediated TLR9 activation in immune cells through a direct interaction. Conclusion: These novel findings reveal that histones represent a new class of DAMP molecules and serve as a crucial link between initial damage and activation of innate immunity during sterile inflammation. (HEPATOLOGY 2011; 54:999–1008)
Bibliography:	These authors contributed equally to this work. fax: 412‐692‐2002 Potential conflict of interest: Nothing to report. Supported by a Howard Hughes Medical Institute Physician‐Scientist Award (A. T.), an American College of Surgeons Research Fellowship (A. T.), and a Howard Hughes Medical Institute Research Training for Medical Student Fellowship (J. E.) ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Supported by a Howard Hughes Medical Institute Physician-Scientist Award (A. T.), an American College of Surgeons Research Fellowship (A. T.), and a Howard Hughes Medical Institute Research Training for Medical Student Fellowship (J. E.)
ISSN:	0270-9139 1527-3350 1527-3350
DOI:	10.1002/hep.24501