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CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN.

TitleCYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN.
Publication TypeJournal Article
Year of Publication2016
AuthorsLegarda, D, Justus, SJ, Ang, RL, Rikhi, N, Li, W, Moran, TM, Zhang, J, Mizoguchi, E, Zelic, M, Kelliher, MA, J Blander, M, Ting, AT
JournalCell Rep
Volume15
Issue11
Pagination2449-61
Date Published2016 Jun 14
ISSN2211-1247
Abstract

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.

DOI10.1016/j.celrep.2016.05.032
Alternate JournalCell Rep
PubMed ID27264187
PubMed Central IDPMC4909532
Grant ListT32 AI007647 / AI / NIAID NIH HHS / United States
R01 AI052417 / AI / NIAID NIH HHS / United States
HHSN272201000054C / AI / NIAID NIH HHS / United States
R01 AI075118 / AI / NIAID NIH HHS / United States
R56 AI104521 / AI / NIAID NIH HHS / United States
R01 DK080070 / DK / NIDDK NIH HHS / United States
P01 DK072201 / DK / NIDDK NIH HHS / United States
R56 AI075118 / AI / NIAID NIH HHS / United States
R01 AI095245 / AI / NIAID NIH HHS / United States
T32 AI078892 / AI / NIAID NIH HHS / United States
R56 AI052417 / AI / NIAID NIH HHS / United States