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Cell Rep. 2019 Aug 27;28(9):2275-2287.e5. doi: 10.1016/j.celrep.2019.07.077.

RIPK3 Activation Leads to Cytokine Synthesis that Continues after Loss of Cell Membrane Integrity.

Author information

1
Department of Immunology, University of Washington, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA.
2
Department of Immunology, University of Washington, Seattle, WA 98109, USA.
3
Department of Immunology, Pasteur Institute, 75724 Paris, France.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080, USA.
6
Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
8
Department of Immunology, University of Washington, Seattle, WA 98109, USA. Electronic address: oberst@uw.edu.

Abstract

Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3 and subsequent cell membrane permeabilization by the effector MLKL. RIPK3 activation can also promote immune responses via production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells even after they have lost cell membrane integrity and irreversibly committed to death. This continued cytokine production is dependent on mRNA translation and requires maintenance of endoplasmic reticulum integrity that remains after plasma membrane integrity is lost. The continued translation of cytokines by cellular corpses contributes to necroptotic cell uptake by innate immune cells and priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells.

KEYWORDS:

MLKL; RIPK3; cell death; cytokines; necroptosis; phagocytosis

PMID:
31461645
PMCID:
PMC6857709
[Available on 2020-02-27]
DOI:
10.1016/j.celrep.2019.07.077
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