MCC950 blocks enhanced interleukin-1β production in patients with NLRP3 low penetrance variants.
Adult
Cells, Cultured
Cranial Nerves
/ immunology
Female
Follow-Up Studies
Furans
/ pharmacology
Hereditary Autoinflammatory Diseases
/ genetics
Heterocyclic Compounds, 4 or More Rings
Humans
Indenes
Inflammasomes
/ metabolism
Interleukin-1beta
/ metabolism
Interleukin-6
/ metabolism
Leukocytes, Mononuclear
/ physiology
Male
Middle Aged
Molecular Targeted Therapy
Mutation
/ genetics
NLR Family, Pyrin Domain-Containing 3 Protein
/ antagonists & inhibitors
Nervous System Diseases
/ genetics
Penetrance
Sulfonamides
/ pharmacology
Sulfones
Tumor Necrosis Factor-alpha
/ metabolism
Autoimmunity
Autoinflammation
IL-1β
MCC950
NLRP3 low penetrance mutations
Journal
Clinical immunology (Orlando, Fla.)
ISSN: 1521-7035
Titre abrégé: Clin Immunol
Pays: United States
ID NLM: 100883537
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
03
12
2018
revised:
05
04
2019
accepted:
05
04
2019
pubmed:
12
4
2019
medline:
3
4
2020
entrez:
12
4
2019
Statut:
ppublish
Résumé
To determine the role of the NLRP3 inflammasome by using the selective NLRP3 inhibitor MCC950 in patients with NLRP3 low penetrance variants and clinical symptoms suggestive for an autoinflammatory syndrome including central nervous system (CNS) involvement. Nineteen symptomatic patients with low penetrance NLRP3 variants (Q703K n = 17, V198M n = 2) recruited between 2011 and 2017 were included in this monocentric study. A functional inflammasome activation assay was performed in patients in comparison to healthy controls (HC), including the determination of interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) secretion in the presence of the NLRP3 selective small-molecule inhibitor MCC950. Detailed clinical features were assessed and anti-IL-1 treatment response was determined. Peripheral blood mononuclear cells (PBMC) from patients with low penetrance NLRP3 variants displayed enhanced IL-1β levels following inflammasome activation compared to HC. Furthermore, IL-1β release was NLRP3-dependent as it was blocked by MCC950. The production of IL-6 and TNF-α was also increased in patients with low penetrance NLRP3 variants. Clinically, they presented with a heterogenous spectrum of neurological manifestations, while cranial nerve inflammation was the most common feature. Overall inflammasome activation did not correlate with disease severity. Eight of ten treated patients responded to anti IL-1 treatment, however a complete response was only documented in four patients. PBMC of several patients with NLRP3 low penetrance variants and CNS manifestation showed increased NLRP3-specific IL-1β release upon stimulation and elevated NLRP3-independent IL-6 and TNF-α levels as those were not suppressed by MCC950. Our data suggest that beside the possible causal involvement of the NLRP3 inflammasome additional, yet unidentified genetic or environmental factors may contribute to the multi-organ inflammation in our patients and explain the partial response to IL-1 targeting therapies.
Identifiants
pubmed: 30974290
pii: S1521-6616(18)30700-9
doi: 10.1016/j.clim.2019.04.004
pii:
doi:
Substances chimiques
Furans
0
Heterocyclic Compounds, 4 or More Rings
0
Indenes
0
Inflammasomes
0
Interleukin-1beta
0
Interleukin-6
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
NLRP3 protein, human
0
Sulfonamides
0
Sulfones
0
Tumor Necrosis Factor-alpha
0
N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
6RS86E2BWQ
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
45-52Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.