Immunometabolic modulation of retinal inflammation by CD36 ligand.
Animals
Biomarkers
CD36 Antigens
/ metabolism
Cytokines
/ metabolism
Disease Susceptibility
Energy Metabolism
/ drug effects
Immunomodulation
/ drug effects
Inflammasomes
/ metabolism
Inflammation Mediators
/ metabolism
Ligands
Metabolome
Metabolomics
/ methods
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Photoreceptor Cells, Vertebrate
/ metabolism
Protein Binding
Retinitis
/ etiology
Signal Transduction
/ drug effects
Toll-Like Receptor 2
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
09 09 2019
09 09 2019
Historique:
received:
29
11
2018
accepted:
20
08
2019
entrez:
11
9
2019
pubmed:
11
9
2019
medline:
28
10
2020
Statut:
epublish
Résumé
In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mice featured less subretinal MP accumulation and attenuated photoreceptor degeneration. Moreover, treatment with a CD36-selective azapeptide ligand (MPE-001) reduced subretinal activated MP accumulation in wild type mice and preserved photoreceptor layers and function as assessed by electroretinography in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal activated MP by reducing pro-inflammatory markers. In isolated MP, MPE-001 induced dissociation of the CD36-Toll-like receptor 2 (TLR2) oligomeric complex, decreasing nuclear factor-kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In addition, MPE-001 caused an aerobic metabolic shift in activated MP, involving peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, which in turn mitigated inflammation. Accordingly, PPAR-γ inhibition blocked the cytoprotective effect of MPE-001 on photoreceptor apoptosis elicited by activated MP. By altering activated MP metabolism, MPE-001 decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury characteristic of various vision-threatening retinal disorders.
Identifiants
pubmed: 31501473
doi: 10.1038/s41598-019-49472-8
pii: 10.1038/s41598-019-49472-8
pmc: PMC6733801
doi:
Substances chimiques
Biomarkers
0
CD36 Antigens
0
Cytokines
0
Inflammasomes
0
Inflammation Mediators
0
Ligands
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Toll-Like Receptor 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12903Subventions
Organisme : CIHR
ID : PPP-90157
Pays : Canada
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