UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network

Date

6-14-2016

Document Type

Article

Disciplines

Cancer Biology | Cell Biology

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.

Rights and Permissions

Citation: Cell Rep. 2016 Jun 14;15(11):2449-61. doi: 10.1016/j.celrep.2016.05.032. Epub 2016 Jun 2. Link to article on publisher's site

DOI of Published Version

10.1016/j.celrep.2016.05.032

Related Resources

Link to Article in PubMed

Journal Title

Cell reports

PubMed ID

27264187

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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