Evidence map›Paper›PMID 29786074›Full record

ArticleCell death and differentiation2019

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

Joseph Sarhan, Beiyun C Liu, Hayley I Muendlein, Chi G Weindel, Irina Smirnova, Amy Y Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A Fitzgerald and 1 more

Open access · hybridAbstract read
In one paragraph

Article in Cell death and differentiation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers.

0numbers the graph read from it
0cells of the map it votes in
109citing papers in PubMed
6.8field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

109 citing papers in PubMed, 179 citations in OpenAlex.

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  14. bioRxiv : the preprint server for biology · 2025
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  17. ZBP1-driven cell death in severe influenza.Trends in microbiology · 2025
    Review
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49 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 6 institutions in 2 countries.

Joseph SarhanMedical Scientist Training Program (MSTP), Tufts University School of Medicine, Boston, MA, 02111, USA.
Beiyun C LiuGraduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA.
Hayley I MuendleinGraduate Program in Genetics, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA.
Chi G WeindelDepartment of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, TX, 77808, USA.
Irina SmirnovaDepartment of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA.
Amy Y TangDepartment of Immunology, Tufts University School of Medicine, Boston, MA, 02111, USA.
Vladimir IlyukhaPetrozavodsk State University, Petrozavodsk, Republic of Karelia, 185910, Russia.
Maxim SorokinNational Research Center, Kurchatov Institute, Moscow, Russian Federation.
Anton BuzdinNational Research Center, Kurchatov Institute, Moscow, Russian Federation.
Katherine A FitzgeraldProgram in Innate Immunity, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Alexander PoltorakGraduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA, 02111, USA. Alexander.Poltorak@tufts.edu.
Tufts University · USPetrozavodsk State University · RUKurchatov Institute · RUSechenov University · RUTexas A&M Health Science Center · USUniversity of Massachusetts Chan Medical School · US

Funding

Hyper-Responsiveness to TLR Agonists in Wild Derived MiceR01AI056234 · NIAID · TUFTS UNIVERSITY BOSTON · PI POLTORAK, ALEXANDER · 2003 to 2023
$8.4M
Gene Regulation in Innate ImmunityR37AI067497 · NIAID · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI FITZGERALD, KATHERINE A. · 2015 to 2024
$4.6M
IMMUNOLOGIC ASPECTS OF DISEASET32AI007077 · NIAID · TUFTS UNIVERSITY BOSTON · PI WORTIS, HENRY H. · 1985 to 2017
$3.5M
Activation of STING-mediated pathway(s) in T cellsR21AI119833 · NIAID · TUFTS UNIVERSITY BOSTON · PI POLTORAK, ALEXANDER · 2016 to 2017
$454k
The regulation of basal interferon and its role in necroptosisR21AI126050 · NIAID · TUFTS UNIVERSITY BOSTON · PI POLTORAK, ALEXANDER · 2016 to 2017
$454k
DNA-RESPONSES IN WILD-DERIVED MICER21AI135369 · NIAID · TUFTS UNIVERSITY BOSTON · PI POLTORAK, ALEXANDER · 2018 to 2019
$454k
NIAID NIH HHS R01 AI056234NIAID NIH HHS R21 AI119833NIAID NIH HHS R21 AI126050NIAID NIH HHS R21 AI135369NIAID NIH HHS R37 AI067497NIAID NIH HHS T32 AI007077
6 · The paper itself

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.

Indexed as

NecroptosisAnimalsCells, CulturedCell SurvivalCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseCytosolDNAGene Knockout TechniquesHumansInterferon-betaLipopolysaccharidesMacrophagesMembrane ProteinsMiceMice, Inbred C57BLMice, KnockoutcGAS protein, mouseCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseDNAInterferon-betaLipopolysaccharidesMembrane ProteinsMLKL protein, humanMLKL protein, mouseNucleotidyltransferasesProtein KinasesSting1 protein, mouseSTING Protein

Identifiers

PMID29786074
PMCPMC6329789
OpenAlexW2804257663

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.