CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN.
Tumor necrosis factor (TNF) induces necroptosis, a RIPK3/MLKL-dependent form of inflammatory cell death. In response to infection by Gram-negative bacteria, multiple receptors on macrophages, including TLR4, TNF, and type I IFN receptors, are concurrently activated, but it is unclear how they crosstalk to regulate necroptosis. We report that TLR4 activates CASPASE-8 to cleave and remove the deubiquitinase cylindromatosis (CYLD) in a TRIF- and RIPK1-dependent manner to disable necroptosis in macrophages. Inhibiting CASPASE-8 leads to CYLD-dependent necroptosis caused by the TNF produced in response to TLR4 ligation. While lipopolysaccharides (LPS)-induced necroptosis was abrogated in Tnf(-/-) macrophages, a soluble TNF antagonist was not able to do so in Tnf(+/+) macrophages, indicating that necroptosis occurs in a cell-autonomous manner. Surprisingly, TNF-mediated auto-necroptosis of macrophages requires type I IFN, which primes the expression of key necroptosis-signaling molecules, including TNFR2 and MLKL. Thus, the TNF necroptosis pathway is regulated by both negative and positive crosstalk.
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Diana
D
Legarda
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Scott J
SJ
Justus
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Rosalind L
RL
Ang
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nimisha
N
Rikhi
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Wenjing
W
Li
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Thomas M
TM
Moran
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Jianke
J
Zhang
Department of Medicine, Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
Emiko
E
Mizoguchi
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Matija
M
Zelic
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Michelle A
MA
Kelliher
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
J Magarian
JM
Blander
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adrian.ting@mssm.edu.
Adrian T
AT
Ting
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D019610:Cytoprotection; D000074749:Deubiquitinating Enzyme CYLD; D007370:Interferon Type I / Q000378:metabolism*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009336:Necrosis; D011494:Protein Kinases / Q000378:metabolism; D059748:Proteolysis; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D053181:Caspase 8; D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D007370:Interferon Type I; D008070:Lipopolysaccharides; D011494:Protein Kinases; D047889:Receptors, Tumor Necrosis Factor, Type II; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse; C570694:MLKL protein, mouse; C511601:CYLD protein, mouse