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Cell Death Differ. 2019 Jan;26(2):332-347. doi: 10.1038/s41418-018-0122-7. Epub 2018 May 21.

Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis.

Author information

1
Medical Scientist Training Program (MSTP), Tufts University School of Medicine, Boston, MA, 02111, USA.
2
Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA.
3
Graduate Program in Genetics, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA.
4
Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77808, USA.
5
Department of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA.
6
Petrozavodsk State University, Petrozavodsk, Republic of Karelia, 185910, Russia.
7
National Research Center, Kurchatov Institute, Moscow, Russian Federation.
8
I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation.
9
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
10
Centre for Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, NTNU, 7491, Trondheim, Norway.
11
Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA. Alexander.Poltorak@tufts.edu.
12
Graduate Program in Genetics, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA. Alexander.Poltorak@tufts.edu.
13
Department of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA. Alexander.Poltorak@tufts.edu.
14
Petrozavodsk State University, Petrozavodsk, Republic of Karelia, 185910, Russia. Alexander.Poltorak@tufts.edu.

Abstract

Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS/STING, and maintains the expression of MLKL and one or more unknown effectors above a critical threshold to allow for MLKL oligomerization and cell death. Finally, we found that elevated IFN-signaling in systemic lupus erythematosus (SLE) augments necroptosis, providing a link between pathological IFN and tissue damage during autoimmunity.

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