title: Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors.
abstract: 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.
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Gehrke
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Garcia-Bardon
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mann
authors.affiliation: Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schad
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Alt
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Wörns
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: M F
authors.initials: MF
authors.lastname: Sprinzl
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Zimmermann
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Menke
authors.affiliation: SD Model Systems of Molecular Nutrition, Friedrich-Schiller University, Jena, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Engstler
authors.affiliation: SD Model Systems of Molecular Nutrition, Friedrich-Schiller University, Jena, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Bergheim
authors.affiliation: Department of Immunology, Duke University, Durham, NC, USA.
authors.forename: Y-W
authors.initials: YW
authors.lastname: He
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: P R
authors.initials: PR
authors.lastname: Galle
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schuchmann
authors.affiliation: I. Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Schattenberg
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate; D017114:Liver Failure, Acute / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D000099197:STING Protein
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D008565:Membrane Proteins; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C506387:Cflar protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse