Title | CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Legarda, D, Justus, SJ, Ang, RL, Rikhi, N, Li, W, Moran, TM, Zhang, J, Mizoguchi, E, Zelic, M, Kelliher, MA, J Blander, M, Ting, AT |
Journal | Cell Rep |
Volume | 15 |
Issue | 11 |
Pagination | 2449-61 |
Date Published | 2016 Jun 14 |
ISSN | 2211-1247 |
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. |
DOI | 10.1016/j.celrep.2016.05.032 |
Alternate Journal | Cell Rep |
PubMed ID | 27264187 |
PubMed Central ID | PMC4909532 |
Grant List | T32 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 |