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Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors.

Publication ,  Journal Article
Gehrke, N; Garcia-Bardon, D; Mann, A; Schad, A; Alt, Y; Wörns, MA; Sprinzl, MF; Zimmermann, T; Menke, J; Engstler, AJ; Bergheim, I; He, Y-W ...
Published in: Cell Death Differ
May 2015

Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the anti-apoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and anti-inflammatory therapies in acute organ failure.

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Published In

Cell Death Differ

DOI

EISSN

1476-5403

Publication Date

May 2015

Volume

22

Issue

5

Start / End Page

826 / 837

Location

England

Related Subject Headings

  • Toll-Like Receptor 9
  • Toll-Like Receptor 4
  • Mice, Transgenic
  • Mice
  • Membrane Proteins
  • Macrophages
  • Liver Failure, Acute
  • Immunity, Innate
  • Hepatocytes
  • CASP8 and FADD-Like Apoptosis Regulating Protein
 

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Gehrke, N., Garcia-Bardon, D., Mann, A., Schad, A., Alt, Y., Wörns, M. A., … Schattenberg, J. M. (2015). Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors. Cell Death Differ, 22(5), 826–837. https://doi.org/10.1038/cdd.2014.178
Gehrke, N., D. Garcia-Bardon, A. Mann, A. Schad, Y. Alt, M. A. Wörns, M. F. Sprinzl, et al. “Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors.Cell Death Differ 22, no. 5 (May 2015): 826–37. https://doi.org/10.1038/cdd.2014.178.
Gehrke N, Garcia-Bardon D, Mann A, Schad A, Alt Y, Wörns MA, et al. Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors. Cell Death Differ. 2015 May;22(5):826–37.
Gehrke, N., et al. “Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors.Cell Death Differ, vol. 22, no. 5, May 2015, pp. 826–37. Pubmed, doi:10.1038/cdd.2014.178.
Gehrke N, Garcia-Bardon D, Mann A, Schad A, Alt Y, Wörns MA, Sprinzl MF, Zimmermann T, Menke J, Engstler AJ, Bergheim I, He Y-W, Galle PR, Schuchmann M, Schattenberg JM. Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors. Cell Death Differ. 2015 May;22(5):826–837.

Published In

Cell Death Differ

DOI

EISSN

1476-5403

Publication Date

May 2015

Volume

22

Issue

5

Start / End Page

826 / 837

Location

England

Related Subject Headings

  • Toll-Like Receptor 9
  • Toll-Like Receptor 4
  • Mice, Transgenic
  • Mice
  • Membrane Proteins
  • Macrophages
  • Liver Failure, Acute
  • Immunity, Innate
  • Hepatocytes
  • CASP8 and FADD-Like Apoptosis Regulating Protein