The latest study from the Jill Roberts Institute, "A Cellular Tango: Immune and Nerve Cells Work Together to Fight Gut Infections," was published on September 6 in Nature. To read more, click here.     Dr. Gregory Sonnenberg wins inaugural award from the Society for Mucosal Immunology. To read more, click here.        

The Jill Roberts Institute for Research in Inflammatory Bowel Disease

You are here

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