TYK2 licenses non-canonical inflammasome activation during endotoxemia.
Animals
Caspases, Initiator
/ metabolism
Endotoxemia
/ drug therapy
Female
Humans
Inflammasomes
/ drug effects
Interleukin-18
/ metabolism
Interleukin-1beta
/ metabolism
Lipopolysaccharides
/ toxicity
Macrophages
/ drug effects
Mice
Mice, Inbred C57BL
Myeloid Cells
/ drug effects
Pyroptosis
/ drug effects
TYK2 Kinase
/ pharmacology
U937 Cells
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
07
01
2020
accepted:
01
09
2020
revised:
31
08
2020
pubmed:
16
9
2020
medline:
16
12
2021
entrez:
15
9
2020
Statut:
ppublish
Résumé
The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.
Identifiants
pubmed: 32929218
doi: 10.1038/s41418-020-00621-x
pii: 10.1038/s41418-020-00621-x
pmc: PMC7862449
doi:
Substances chimiques
Inflammasomes
0
Interleukin-18
0
Interleukin-1beta
0
Lipopolysaccharides
0
TYK2 Kinase
EC 2.7.10.2
TYK2 protein, human
EC 2.7.10.2
Casp4 protein, mouse
EC 3.4.22.-
Caspases, Initiator
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
748-763Subventions
Organisme : Austrian Science Fund FWF
ID : F 6101
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : F 6106
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : DOC 32
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 25642
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : F 6105
Pays : Austria
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