Age-Dependent Changes in FasL (CD95L) Modulate Macrophage Function in a Model of Age-Related Macular Degeneration

Zhao, Hui; Roychoudhury, Jayeeta; Doggett, Teresa A.; Apte, Rajendra S.; Ferguson, T.

doi:10.1167/iovs.13-12122

Cited by 39 publications

(36 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast to prior work, in which IL-10-treated macrophages failed to reduce CNV (Kelly et al, 2007), our results showed that M2-differentiated macrophages significantly increase CNV. Importantly, the mechanism shown in this work is distinct from the prior concept of differential recruitment of macrophage subtypes in CNV (Zhao et al, 2013), since ROCK2 does not affect macrophage recruitment.…”

Section: Discussioncontrasting

confidence: 54%

ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration

et al. 2015

View full text Add to dashboard Cite

Age is a major risk factor in age-related macular degeneration (AMD), but the underlying cause is unknown. We find increased Rho-associated kinase (ROCK) signaling and M2 characteristics in eyes of aged mice, revealing immune changes in aging. ROCK isoforms determine macrophage polarization into M1 and M2 subtypes. M2-like macrophages accumulated in AMD, but not in normal eyes, suggesting these macrophages may be linked to macular degeneration. M2 macrophages injected into the mouse eye exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them, supporting a causal role for macrophage subtypes in AMD. Selective ROCK2 inhibition with a small molecule decreased M2-like macrophages and choroidal neovascularization. ROCK2 inhibition upregulated M1 markers without affecting macrophage recruitment, underlining the plasticity of these macrophages. These results reveal age-induced innate immune imbalance as underlying AMD pathogenesis. Targeting macrophage plasticity opens up new possibilities for more effective AMD treatment.

show abstract

Section: Discussioncontrasting

confidence: 54%

ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration

et al. 2015

View full text Add to dashboard Cite

show abstract

“…However, a previous study that used pharmacological macrophage depletion with liposomal clodronate demonstrated the contribution of macrophages to CNV development: phagocytosis of liposomal clodronate by macrophages rapidly induced apoptosis without proinflammatory cytokine secretion and resulted in CNV suppression [31]. Macrophages can also be antiangiogenic depending on their condition; the intensity of the CNV development may be relied on a balance between M1 and M2 macrophages [38][39][40]. The macrophages that we observed during CNV development might have included both types.…”

Section: Discussionmentioning

confidence: 69%

Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

Nagai

Kubota

Tsubota

et al. 2014

The Journal of Nutritional Biochemistry

View full text Add to dashboard Cite

The development of choroidal neovascularization (CNV) is a critical step in the pathogenesis of age-related macular degeneration (AMD), a vision-threatening disease. In this study, we used a mouse model of AMD to study the protective effects of resveratrol (RSV) supplementation against CNV as well as the underlying molecular mechanisms. Mice were orally pretreated with RSV daily for 5 days. On the fifth day, the mice underwent laser photocoagulation to induce CNV. One week after laser treatment, CNV volume was significantly lower in the RSV-treated mice compared with vehicle-treated animals. In addition, RSV treatment significantly inhibited macrophage infiltration into the retinal pigment epithelium (RPE)-choroid and suppressed the expression of inflammatory and angiogenic molecules, including vascular endothelial growth factor, monocyte chemotactic protein-1 and intercellular adhesion molecule-1. Importantly, RSV prevented the CNV-induced decrease in activated AMP-activated protein kinase and increase in activated nuclear factor-κB in the RPE-choroid complex. The regulatory effects of RSV on these molecules were confirmed in RPE, microvascular endothelial and macrophage cell lines. Inhibition of macrophage infiltration by RSV was confirmed by in vitro scratch and migration assays. RSV suppressed CNV development, reducing the levels of multiple cytokines secreted from several cell types and inhibiting macrophage migration. The direct effects of RSV on each cell type were confirmed in vitro. Although further studies are needed, RSV could potentially be applied in the clinic to prevent CNV development in AMD.

show abstract

“…They have an important role in clearance of debris and in the regulation of inflammatory signalling and tissue homeostasis (Xu et al, 2008; Wang et al, 2009; Xu et al, 2009; Zhao et al, 2013). In young and healthy animals, the number of macrophages and microglia are low in the retinal space and they have beneficial effects on the clearance process and in the regulation of para-inflammation (Xu et al, 2009).…”

Section: 0 Dysregulation Of Clearance Systems: Progression From Parmentioning

confidence: 99%

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Ferrington

Sinha

Kaarniranta

2016

Progress in Retinal and Eye Research

192

229

View full text Add to dashboard Cite

Maintenance of protein homeostasis, also referred to as “Proteostasis”, integrates multiple pathways that regulate protein synthesis, folding, translocation, and degradation. Failure in proteostasis may be one of the underlying mechanisms responsible for the cascade of events leading to age-related macular degeneration (AMD). This review covers the major degradative pathways (ubiquitin-proteasome and lysosomal involvement in phagocytosis and autophagy) in the retinal pigment epithelium (RPE) and summarizes evidence of their involvement in AMD. Degradation of damaged and misfolded proteins via the proteasome occurs in coordination with heat shock proteins. Evidence of increased content of proteasome and heat shock proteins in retinas from human donors with AMD is consistent with increased oxidative stress and extensive protein damage with AMD. Phagocytosis and autophagy share key molecules in phagosome maturation as well as degradation of their cargo following fusion with lysosomes. Phagocytosis and degradation of photoreceptor outer segments ensures functional integrity of the neural retina. Autophagy rids the cell of toxic protein aggregates and defective mitochondria. Evidence suggesting a decline in autophagic flux includes the accumulation of autophagic substrates and damaged mitochondria in RPE from AMD donors. An age-related decrease in lysosomal enzymatic activity inhibits autophagic clearance of outer segments, mitochondria, and protein aggregates, thereby accelerating the accumulation of lipofuscin. This cumulative damage over a person’s lifetime tips the balance in RPE from a state of para-inflammation, which strives to restore cell homeostasis, to the chronic inflammation associated with AMD.

show abstract

Age-Dependent Changes in FasL (CD95L) Modulate Macrophage Function in a Model of Age-Related Macular Degeneration

Cited by 39 publications

References 69 publications

ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration

ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration

Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Contact Info

Product

Resources

About