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

Research output: Contribution to journalArticle

33 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
Externally publishedYes

Fingerprint

Proteolysis
Macrophages
Lipopolysaccharides
Tumor Necrosis Factor-alpha
Crosstalk
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Gram-Negative Bacteria
Ligation
Cell death
Cell Death
Bacteria
Infection
Molecules

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. / Legarda, Diana; Justus, Scott J.; Ang, Rosalind L.; Rikhi, Nimisha; Li, Wenjing; Moran, Thomas M.; Zhang, Jianke; Mizoguchi, Emiko; Zelic, Matija; Kelliher, Michelle A.; Blander, J. Magarian; Ting, Adrian T.

In: Cell Reports, Vol. 15, No. 11, 14.06.2016, p. 2449-2461.

Research output: Contribution to journalArticle

Legarda, D, Justus, SJ, Ang, RL, Rikhi, N, Li, W, Moran, TM, Zhang, J, Mizoguchi, E, Zelic, M, Kelliher, MA, Blander, JM & Ting, AT 2016, 'CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN', Cell Reports, vol. 15, no. 11, pp. 2449-2461. https://doi.org/10.1016/j.celrep.2016.05.032
Legarda, Diana ; Justus, Scott J. ; Ang, Rosalind L. ; Rikhi, Nimisha ; Li, Wenjing ; Moran, Thomas M. ; Zhang, Jianke ; Mizoguchi, Emiko ; Zelic, Matija ; Kelliher, Michelle A. ; Blander, J. Magarian ; Ting, Adrian T. / CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. In: Cell Reports. 2016 ; Vol. 15, No. 11. pp. 2449-2461.
@article{5490254ea4ee459a902b49be8b7194cd,
title = "CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN",
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.",
author = "Diana Legarda and Justus, {Scott J.} and Ang, {Rosalind L.} and Nimisha Rikhi and Wenjing Li and Moran, {Thomas M.} and Jianke Zhang and Emiko Mizoguchi and Matija Zelic and Kelliher, {Michelle A.} and Blander, {J. Magarian} and Ting, {Adrian T.}",
year = "2016",
month = "6",
day = "14",
doi = "10.1016/j.celrep.2016.05.032",
language = "English",
volume = "15",
pages = "2449--2461",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",

}

TY - JOUR

T1 - CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN

AU - Legarda, Diana

AU - Justus, Scott J.

AU - Ang, Rosalind L.

AU - Rikhi, Nimisha

AU - Li, Wenjing

AU - Moran, Thomas M.

AU - Zhang, Jianke

AU - Mizoguchi, Emiko

AU - Zelic, Matija

AU - Kelliher, Michelle A.

AU - Blander, J. Magarian

AU - Ting, Adrian T.

PY - 2016/6/14

Y1 - 2016/6/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84974694612&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84974694612&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.05.032

DO - 10.1016/j.celrep.2016.05.032

M3 - Article

VL - 15

SP - 2449

EP - 2461

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -