Potent T cell-mediated anti-inflammatory role of the selective CB2 agonist lenabasum in multiple sclerosis.
Adult
Animals
Anti-Inflammatory Agents
/ pharmacology
Apoptosis
/ drug effects
Cannabinoid Receptor Agonists
/ pharmacology
Cell Survival
/ drug effects
Dronabinol
/ analogs & derivatives
Encephalomyelitis, Autoimmune, Experimental
/ immunology
Female
Humans
Male
Mice
Multiple Sclerosis, Relapsing-Remitting
/ immunology
Receptor, Cannabinoid, CB2
/ agonists
T-Lymphocyte Subsets
/ drug effects
Th1
Th17
cannabinoid receptor
cytokines
multiple sclerosis
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
27
08
2021
received:
15
05
2021
accepted:
14
09
2021
pubmed:
21
9
2021
medline:
1
4
2022
entrez:
20
9
2021
Statut:
ppublish
Résumé
Lenabasum is a synthetic cannabinoid receptor type-2 (CB2) agonist able to exert potent anti-inflammatory effects, but its role on T cells remains unknown. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum in T lymphocyte subsets and its in vivo therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Mononuclear cells from 17 healthy subjects (HS) and 25 relapsing-remitting multiple sclerosis (RRMS) patients were activated in presence or absence of lenabasum and analysed by flow cytometry and qRT-PCR. EAE mice were treated with lenabasum, and clinical score and neuroinflammation were evaluated. Lenabasum significantly reduced TNF-a production from CD4+ T cells and CD8+ T cells in a dose-dependent manner in both HS and RRMS patients. In MS patients, lenabasum also reduced activation marker CD25 and inhibited IL-2 production from both T cell subsets and IFN-γ and IL-17 from committed Th1 and Th17 cells, respectively. These effects were blocked by the pretreatment with selective CB2 inverse agonist SR144528. In vivo treatment of EAE mice with lenabasum significantly ameliorated disease severity, reduced neuroinflammation and demyelination in spinal cord. Lenabasum exerts potent T cell-mediated immunomodulatory effects, suggesting CB2 as a promising pharmacological target to counteract neuroinflammation in MS.
Sections du résumé
BACKGROUND
Lenabasum is a synthetic cannabinoid receptor type-2 (CB2) agonist able to exert potent anti-inflammatory effects, but its role on T cells remains unknown.
OBJECTIVES
The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum in T lymphocyte subsets and its in vivo therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE).
METHODS
Mononuclear cells from 17 healthy subjects (HS) and 25 relapsing-remitting multiple sclerosis (RRMS) patients were activated in presence or absence of lenabasum and analysed by flow cytometry and qRT-PCR. EAE mice were treated with lenabasum, and clinical score and neuroinflammation were evaluated.
RESULTS
Lenabasum significantly reduced TNF-a production from CD4+ T cells and CD8+ T cells in a dose-dependent manner in both HS and RRMS patients. In MS patients, lenabasum also reduced activation marker CD25 and inhibited IL-2 production from both T cell subsets and IFN-γ and IL-17 from committed Th1 and Th17 cells, respectively. These effects were blocked by the pretreatment with selective CB2 inverse agonist SR144528. In vivo treatment of EAE mice with lenabasum significantly ameliorated disease severity, reduced neuroinflammation and demyelination in spinal cord.
CONCLUSION
Lenabasum exerts potent T cell-mediated immunomodulatory effects, suggesting CB2 as a promising pharmacological target to counteract neuroinflammation in MS.
Substances chimiques
Anti-Inflammatory Agents
0
Cannabinoid Receptor Agonists
0
Receptor, Cannabinoid, CB2
0
Dronabinol
7J8897W37S
lenabasum
OGN7X90BT8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12768Informations de copyright
© 2021 British Neuropathological Society.
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