Abstract
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.
Highlights
Inflammation is a critical component in degenerative retinal diseases independent of underlying pathological mechanism[1]
IBA-1+ cell accumulation in the subretina was significantly decreased by 60% in blue light-challenged cluster of differentiation 36 receptor (CD36)+/+ mice treated with MPE-001 compared to vehicle-treated CD36+/+ mice (Fig. 1A,C)
Toll-like receptor 2 (TLR2) pro-inflammatory function has been postulated to contribute to retinal pigment epithelium (RPE) apoptosis due to inflammation and oxidant stress[8]
Summary
Inflammation is a critical component in degenerative retinal diseases independent of underlying pathological mechanism[1]. The ensuing inflammatory cascade is integral for the ultimate death of photoreceptor cells in progressive vision-threatening maladies, including retinitis pigmentosa, diabetic retinopathy and age-related macular degeneration[4,5]. In this context, injured tissues produce damage-associated molecular patterns (DAMPS) that activate Toll-like receptors (TLRs)[6,7] upregulating and sustaining release of pro-inflammatory cytokines and chemokines, which propagate into chronic inflammation resulting in degeneration of retinal pigment epithelium (RPE) and photoreceptors[8]. Immune-metabolic modulation by CD36 ligands, such as MPE-001, offers a promising new means for curbing chronic inflammation characteristic of degenerative eye diseases
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