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.
N1 - Funding Information:
We thank Dr. Shizuo Akira, Dr. Douglas Green, Dr. Shao-Cong Sun, and Dr. Adolfo Garcia-Sastre for providing mice and femurs/tibia, Dr. Nicolas Barnich for providing AIEC strain LF82, and Dr. Kate Fitzgerald for providing J2 virus. We would also like to thank Dr. Marie Anne O’Donnell for helpful discussions. This work was supported by NIH grants AI052417, AI104521, DK072201 (A.T.T.), DK080070 (E.M.), AI095245, DK072201 (J.M.B.), AI075118 (M.A.K.), and National Institute of Allergy and Infectious Diseases (NIAID) contract HHSN272201000054C (T.M.M). This work is also supported by a Senior Research Award 253097 from the Crohn’s and Colitis Foundation of America (A.T.T.). D.L. is a recipient of a Career Development Award from the Crohn’s and Colitis Foundation of America. S.J.J. is supported in part by a Public Health Service Institutional Research Training Award (AI07647) and a Helmsley Trust fellowship. E.M. is supported by a grant from the Broad Medical Foundation (E.M.). J.M.B. is supported by the Burroughs Wellcome Trust Fund, the Leukemia and Lymphoma Society, and the Irma-Hirschl and Monique Weill-Caulier Charitable Trust Funds. R.L.A. is supported by a NIAID T32 Cross-Disciplinary Training Program in Transplant Research (AI78892).
Publisher Copyright:
© 2016 The Author(s).
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.
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U2 - 10.1016/j.celrep.2016.05.032
DO - 10.1016/j.celrep.2016.05.032
M3 - Article
C2 - 27264187
AN - SCOPUS:84974694612
VL - 15
SP - 2449
EP - 2461
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 11
ER -