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

Diana Legarda, Scott J. Justus, Rosalind L. Ang, Nimisha Rikhi, Wenjing Li, Thomas M. Moran, Jianke Zhang, Emiko Mizoguchi, Matija Zelic, Michelle A. Kelliher, J. Magarian Blander, Adrian T. Ting

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41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2449-2461
Number of pages13
JournalCell Reports
Volume15
Issue number11
DOIs
Publication statusPublished - 14 Jun 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Legarda, D., Justus, S. J., Ang, R. L., Rikhi, N., Li, W., Moran, T. M., Zhang, J., Mizoguchi, E., Zelic, M., Kelliher, M. A., Blander, J. M., & Ting, A. T. (2016). CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. Cell Reports, 15(11), 2449-2461. https://doi.org/10.1016/j.celrep.2016.05.032