Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA.
cognitive decline
haematopoietic stem cell gene therapy
inflammasome
interleukin-1 receptor antagonist
mucopolysaccharidosis
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
06 03 2020
06 03 2020
Historique:
received:
24
07
2019
revised:
15
01
2020
accepted:
17
01
2020
pubmed:
15
2
2020
medline:
29
7
2021
entrez:
15
2
2020
Statut:
ppublish
Résumé
Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)-1β and interleukin-1 receptor antagonist (IL-1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease-specific 2-O-sulphated heparan sulphate was essential for priming an IL-1β response via the Toll-like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL-1β secretion. IL-1 blockade in mucopolysaccharidosis IIIA mice using IL-1 receptor type 1 knockout or haematopoietic stem cell gene therapy over-expressing IL-1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL-1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL-1Ra as a potential neuronopathic lysosomal disease treatment.
Identifiants
pubmed: 32057196
doi: 10.15252/emmm.201911185
pmc: PMC7059006
doi:
Substances chimiques
Amyloid beta-Peptides
0
Inflammasomes
0
Interleukin 1 Receptor Antagonist Protein
0
Interleukin-1beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e11185Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Neuroscience Research Institute, University of Manchester
Pays : International
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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