Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease.
Animals
Apoptosis
/ immunology
Caspase 8
/ immunology
Female
Immunity, Innate
/ immunology
Inflammasomes
/ immunology
Inflammation
/ immunology
MAP Kinase Kinase Kinases
/ immunology
Macrophages
/ immunology
Mice
Mice, Knockout
Necroptosis
/ immunology
Pyroptosis
/ immunology
Receptor-Interacting Protein Serine-Threonine Kinases
/ immunology
Signal Transduction
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
02 03 2020
02 03 2020
Historique:
received:
03
09
2019
revised:
22
10
2019
accepted:
18
11
2019
entrez:
24
12
2019
pubmed:
24
12
2019
medline:
30
10
2020
Statut:
ppublish
Résumé
RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity-independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity-independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity-independent necroptosis driven by the RIPK3-MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3-caspase-8 signaling axis-driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity-independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.
Identifiants
pubmed: 31869420
pii: 133533
doi: 10.1084/jem.20191644
pmc: PMC7062518
pii:
doi:
Substances chimiques
Inflammasomes
0
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
MAP Kinase Kinase Kinases
EC 2.7.11.25
MAP kinase kinase kinase 7
EC 2.7.11.25
Caspase 8
EC 3.4.22.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI124346
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163507
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI101935
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI101935
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES005605
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR056296
Pays : United States
Organisme : NIAID NIH HHS
ID : K22 AI127836
Pays : United States
Informations de copyright
© 2019 Malireddi et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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