Immunometabolic modulation of retinal inflammation by CD36 ligand

被引：21

作者：

Mellal, Katia ^{[1
]}

Omri, Samy ^{[2
,3
]}

Mulumba, Mukandila ^{[1
]}

Tahiri, Houda ^{[5
,6
,7
]}

Fortin, Carl ^{[1
]}

Dorion, Marie-France ^{[1
]}

Hung Pham ^{[1
]}

Ramos, Yesica Garcia ^{[4
]}

Zhang, Jinqiang ^{[4
]}

Pundir, Sheetal ^{[5
,6
,7
]}

Joyal, Jean-Sebastien ^{[5
,6
,7
]}

Bouchard, Jean-Francois ^{[8
]}

Sennlaub, Florian ^{[9
]}

Febbraio, Maria ^{[10
]}

Hardy, Pierre ^{[5
,6
,7
]}

Gravel, Simon-Pierre ^{[1
]}

Marleau, Sylvie ^{[1
]}

Lubell, William D. ^{[4
]}

Chemtob, Sylvain ^{[2
,5
,6
,7
]}

Ong, Huy ^{[1
]}

机构：

[1] Univ Montreal, Fac Pharm, Montreal, PQ, Canada

[2] Maisonneuve Rosemont Hosp, Montreal, PQ, Canada

[3] Mperia Therapeut, Montreal, PQ, Canada

[4] Univ Montreal, Dept Chem, Montreal, PQ, Canada

[5] Univ Montreal, Dept Pediat, Montreal, PQ, Canada

[6] Univ Montreal, Dept Ophthalmol, Montreal, PQ, Canada

[7] Univ Montreal, Dept Pharmacol, Montreal, PQ, Canada

[8] Univ Montreal, Sch Optometry, Neuropharmacol Lab, Montreal, PQ, Canada

[9] Sorbonne Univ, Inst Vis, CNRS, INSERM, Paris, France

[10] Univ Alberta, Dept Dent, Edmonton, AB, Canada

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

加拿大健康研究院; 加拿大创新基金会;

关键词：

LOW-DENSITY-LIPOPROTEIN; PPAR-GAMMA; PATTERN-RECOGNITION; INNATE IMMUNITY; RECEPTOR; ACTIVATION; MICROGLIA; AGE; MACROPHAGES; SYSTEM;

D O I：

10.1038/s41598-019-49472-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-kappa B) 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-gamma (PPAR-gamma) activation, which in turn mitigated inflammation. Accordingly, PPAR-gamma 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.

引用

页数：18

共 81 条

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