Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway.
Animals
CARD Signaling Adaptor Proteins
/ genetics
Caspase 1
/ metabolism
Cells, Cultured
Disease Models, Animal
Down-Regulation
/ drug effects
Doxorubicin
/ pharmacology
Humans
Inflammasomes
/ metabolism
Interleukin-1beta
/ genetics
Mice
Mice, Inbred C57BL
Microglia
/ cytology
Myeloid Cells
/ cytology
Myeloid Differentiation Factor 88
/ genetics
NF-kappa B
/ metabolism
NLR Family, Pyrin Domain-Containing 3 Protein
/ genetics
Signal Transduction
Tauopathies
/ metabolism
tau Proteins
/ genetics
ASC
IL-1β
MAPT
MyD88
NLRP3
inflammasomes
microglia
neuroinflammation
tau
tauopathies
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
21 09 2021
21 09 2021
Historique:
received:
11
03
2021
revised:
20
05
2021
accepted:
24
08
2021
entrez:
22
9
2021
pubmed:
23
9
2021
medline:
16
2
2022
Statut:
ppublish
Résumé
Pathological hyperphosphorylation and aggregation of tau (pTau) and neuroinflammation, driven by interleukin-1β (IL-1β), are the major hallmarks of tauopathies. Here, we show that pTau primes and activates IL-1β. First, RNA-sequence analysis suggests paired-helical filaments (PHFs) from human tauopathy brain primes nuclear factor κB (NF-κB), chemokine, and IL-1β signaling clusters in human primary microglia. Treating microglia with pTau-containing neuronal media, exosomes, or PHFs causes IL-1β activation, which is NLRP3, ASC, and caspase-1 dependent. Suppression of pTau or ASC reduces tau pathology and inflammasome activation in rTg4510 and hTau mice, respectively. Although the deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy, ASC deficiency in myeloid cells reduces pTau-induced IL-1β activation and improves cognitive function in hTau mice. Finally, pTau burden co-exists with elevated IL-1β and ASC in autopsy brains of human tauopathies. Together, our results suggest pTau activates IL-1β via MyD88- and NLRP3-ASC-dependent pathways in myeloid cells, including microglia.
Identifiants
pubmed: 34551296
pii: S2211-1247(21)01169-4
doi: 10.1016/j.celrep.2021.109720
pmc: PMC8491766
mid: NIHMS1742921
pii:
doi:
Substances chimiques
CARD Signaling Adaptor Proteins
0
Inflammasomes
0
Interleukin-1beta
0
Myeloid Differentiation Factor 88
0
NF-kappa B
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
tau Proteins
0
Doxorubicin
80168379AG
Caspase 1
EC 3.4.22.36
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
Pagination
109720Subventions
Organisme : NIA NIH HHS
ID : P30 AG013854
Pays : United States
Organisme : NINDS NIH HHS
ID : R24 NS104160
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA118100
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121176
Pays : United States
Organisme : NIA NIH HHS
ID : P20 AG068077
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS116051
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS083704
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS093442
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083704
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072977
Pays : United States
Organisme : NIGMS NIH HHS
ID : K12 GM088021
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS077089
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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