Immune cell targeted fumaric esters support a role of GPR109A as a primary target of monomethyl fumarate in vivo.
Fumarates
GPR109A
Lysosomal Trapping
Macrolides
Psoriasis
Journal
Inflammopharmacology
ISSN: 1568-5608
Titre abrégé: Inflammopharmacology
Pays: Switzerland
ID NLM: 9112626
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
02
12
2022
accepted:
19
02
2023
medline:
1
6
2023
pubmed:
3
4
2023
entrez:
2
4
2023
Statut:
ppublish
Résumé
Dimethyl fumarate (DMF) is approved as a treatment for multiple sclerosis (MS), however, its mode of action remains unclear. One hypothesis proposes that Michael addition to thiols by DMF, notably glutathione is immunomodulatory. The alternative proposes that monomethyl fumarate (MMF), the hydrolysis product of DMF, is a ligand to the fatty acid receptor GPR109A found in the lysosomes of immune cells. We prepared esters of MMF and macrolides derived from azithromycin, which were tropic to immune cells by virtue of lysosomal trapping. We tested the effects of these substances in an assay of response to Lipopolysaccharide (LPS) in freshly isolated human peripheral blood mononuclear cells (PBMCs). In this system, we observed that the 4'' ester of MMF (compound 2 and 3) reduced levels of Interleukins (IL)-1β, IL-12 and tumor necrosis factor alpha (TNFα) significantly at a concentration of 1 µM, while DMF required about 25 µM for the same effect. The 2' esters of MMF (compound 1 and 2) were, like MMF itself, inactive in vitro. The 4'' ester formed glutathione conjugates rapidly while the 2' conjugates did not react with thiols but did hydrolyze slowly to release MMF in these cells. We then tested the substances in vivo using the imiquimod/isostearate model of psoriasis where the 2' ester was the most active at 0.06-0.12 mg/kg (approximately 0.1 µmol/kg), improving skin score, body weight and cytokine levels (TNFα, IL-17A, IL-17F, IL-6, IL-1β, NLRP3 and IL-23A). In contrast, the thiol reactive 4'' ester was less active than the 2' ester while DMF was ca. 300-fold less active. The thiol reactive 4'' ester was not easily recovered from either plasma or organs while the 2' ester exhibited conventional uptake and elimination. The 2' ester also reduced levels of IL-6 in acute monosodium urate (MSU) induced inflammation. These data suggest that mechanisms that are relevant in vivo center on the release of MMF. Given that GPR109A is localized to the lysosome, and that lysosomal trapping increases 2' ester activity by > 300 fold, these data suggest that GPR109A may be the main target in vivo. In contrast, the effects associated with glutathione (GSH) conjugation in vitro are unlikely to be as effective in vivo due to the much lower dose in use which cannot titrate the more concentrated thiols. These data support the case for GPR109A modulation in autoimmune diseases.
Identifiants
pubmed: 37004600
doi: 10.1007/s10787-023-01186-0
pii: 10.1007/s10787-023-01186-0
doi:
Substances chimiques
monomethyl fumarate
45IUB1PX8R
Esters
0
Interleukin-6
0
Tumor Necrosis Factor-alpha
0
citraconic acid
0RQ6CXO9KD
Dimethyl Fumarate
FO2303MNI2
Glutathione
GAN16C9B8O
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1223-1239Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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