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TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation

Dmitri Krysko UGent, Agnieszka Kaczmarek UGent, Olga Krysko UGent, Liesbeth Heyndrickx UGent, Jerzy Woznicki UGent, Pieter Bogaert UGent, Anje Cauwels UGent, Nozomi Takahashi UGent, S Magez and Claus Bachert UGent, et al. (2011) CELL DEATH AND DIFFERENTIATION. 18(8). p.1316-1325
abstract
Anthracycline antibiotics are inducers of an immunogenic form of apoptosis that has immunostimulatory properties because of the release of damage-associated molecular patterns. To study the mechanisms used by the innate immune system to sense this immunogenic form of cell death, we established an in vivo model of cell death induced by intraperitoneal injection of doxorubicin, a prototype of anthracyclines. The acute sterile inflammation in this model is characterized by rapid influx of neutrophils and increased levels of IL-6 and monocyte chemotactic protein-1. We demonstrate that acute inflammation induced by doxorubicin is associated with apoptosis of monocytes/macrophages and that it is specific for doxorubicin, an immunogenic chemotherapeutic. Further, the inflammatory response is significantly reduced in mice deficient in myeloid differentiation primary response gene 88 (MyD88), TLR-2 or TLR-9. Importantly, a TLR-9 antagonist reduces the recruitment of neutrophils induced by doxorubicin. By contrast, the acute inflammatory response is not affected in TRIF Lps2 mutant mice and in TLR-3, TLR-4 and caspase-1 knockout mice, which shows that the inflammasome does not have a major role in doxorubicin-induced acute inflammation. Our findings provide important new insights into how the innate immune system senses immunogenic apoptotic cells and clearly demonstrate that the TLR-2/TLR-9-MyD88 signaling pathways have a central role in initiating the acute inflammatory response to this immunogenic form of apoptosis
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
NECROTIC CELLS, DYING CELLS, NEUTROPHIL DEPLETION, IMMUNE-SYSTEM, RECOGNITION, CLEARANCE, immunogenic cell death, DAMPs, neutrophils, apoptosis, TLRs, doxorubicin, NECROSIS, INJURY, DEATH, HMGB1
journal title
CELL DEATH AND DIFFERENTIATION
Cell Death Differ.
volume
18
issue
8
pages
1316 - 1325
Web of Science type
Article
Web of Science id
000292634000011
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
8.849 (2011)
JCR rank
23/286 (2011)
JCR quartile
1 (2011)
ISSN
1350-9047
DOI
10.1038/cdd.2011.4
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1870596
handle
http://hdl.handle.net/1854/LU-1870596
date created
2011-08-08 16:48:47
date last changed
2013-02-27 09:09:10
@article{1870596,
  abstract     = {Anthracycline antibiotics are inducers of an immunogenic form of apoptosis that has immunostimulatory properties because of the release of damage-associated molecular patterns. To study the mechanisms used by the innate immune system to sense this immunogenic form of cell death, we established an in vivo model of cell death induced by intraperitoneal injection of doxorubicin, a prototype of anthracyclines. The acute sterile inflammation in this model is characterized by rapid influx of neutrophils and increased levels of IL-6 and monocyte chemotactic protein-1. We demonstrate that acute inflammation induced by doxorubicin is associated with apoptosis of monocytes/macrophages and that it is specific for doxorubicin, an immunogenic chemotherapeutic. Further, the inflammatory response is significantly reduced in mice deficient in myeloid differentiation primary response gene 88 (MyD88), TLR-2 or TLR-9. Importantly, a TLR-9 antagonist reduces the recruitment of neutrophils induced by doxorubicin. By contrast, the acute inflammatory response is not affected in TRIF Lps2 mutant mice and in TLR-3, TLR-4 and caspase-1 knockout mice, which shows that the inflammasome does not have a major role in doxorubicin-induced acute inflammation. Our findings provide important new insights into how the innate immune system senses immunogenic apoptotic cells and clearly demonstrate that the TLR-2/TLR-9-MyD88 signaling pathways have a central role in initiating the acute inflammatory response to this immunogenic form of apoptosis},
  author       = {Krysko, Dmitri and Kaczmarek, Agnieszka and Krysko, Olga and Heyndrickx, Liesbeth and Woznicki, Jerzy and Bogaert, Pieter and Cauwels, Anje and Takahashi, Nozomi and Magez, S and Bachert, Claus and Vandenabeele, Peter},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keyword      = {NECROTIC CELLS,DYING CELLS,NEUTROPHIL DEPLETION,IMMUNE-SYSTEM,RECOGNITION,CLEARANCE,immunogenic cell death,DAMPs,neutrophils,apoptosis,TLRs,doxorubicin,NECROSIS,INJURY,DEATH,HMGB1},
  language     = {eng},
  number       = {8},
  pages        = {1316--1325},
  title        = {TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation},
  url          = {http://dx.doi.org/10.1038/cdd.2011.4},
  volume       = {18},
  year         = {2011},
}

Chicago
Krysko, Dmitri, Agnieszka Kaczmarek, Olga Krysko, Liesbeth Heyndrickx, Jerzy Woznicki, Pieter Bogaert, Anje Cauwels, et al. 2011. “TLR-2 and TLR-9 Are Sensors of Apoptosis in a Mouse Model of Doxorubicin-induced Acute Inflammation.” Cell Death and Differentiation 18 (8): 1316–1325.
APA
Krysko, D., Kaczmarek, A., Krysko, O., Heyndrickx, L., Woznicki, J., Bogaert, P., Cauwels, A., et al. (2011). TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. CELL DEATH AND DIFFERENTIATION, 18(8), 1316–1325.
Vancouver
1.
Krysko D, Kaczmarek A, Krysko O, Heyndrickx L, Woznicki J, Bogaert P, et al. TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. CELL DEATH AND DIFFERENTIATION. 2011;18(8):1316–25.
MLA
Krysko, Dmitri, Agnieszka Kaczmarek, Olga Krysko, et al. “TLR-2 and TLR-9 Are Sensors of Apoptosis in a Mouse Model of Doxorubicin-induced Acute Inflammation.” CELL DEATH AND DIFFERENTIATION 18.8 (2011): 1316–1325. Print.