ADAM17 mediates ectodomain shedding of the soluble VLDL receptor fragment in the retinal epithelium

Ma, Xiang; Takahashi, Yusuke; Wu, Wenjing; Liang, Wentao; Chen, Jianglei; Chakraborty, Dibyendu; Li, Yangxiong; Du, Yanhong; Benyajati, Siribhinya; Ma, Jian-Xing

doi:10.1016/j.jbc.2021.101185

Cited by 8 publications

(8 citation statements)

References 42 publications

(78 reference statements)

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“…4A). Therefore, these findings support our observations on increased Trem2 expression and previous reports of elevated α-secretases, including ADAM10/17 in retinal degeneration as well (54,55).…”

Section: Augmentation Of Trem2 Activity Ameliorates Retinal Degenerat...supporting

confidence: 93%

Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions

Lad

Mathew

et al. 2023

Preprint

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Degenerative diseases of the outer retina, including age-related macular degeneration (AMD), are characterized by atrophy of photoreceptors and retinal pigment epithelium (RPE). In these blinding diseases, macrophages are known to accumulate ectopically at sites of atrophy, but their ontogeny and functional specialization within this atrophic niche remain poorly understood, especially in the human context. Here, we uncovered a transcriptionally unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and in human AMD. Using disease models, we found that conditional deletion of galectin-3 in microglia led to defects in phagocytosis and consequent augmented photoreceptor death, RPE damage and vision loss, suggestive of a protective role. Mechanistically, Trem2 signaling orchestrated the migration of microglial cells to sites of atrophy, and there, induced galectin-3 expression. Moreover, pharmacologic Trem2 agonization led to heightened protection, but only in a galectin-3-dependent manner, further signifying the functional interdependence of these two molecules. Likewise in elderly human subjects, we identified a highly conserved population of microglia at the transcriptomic, protein and spatial levels, and this population was enriched in the macular region of postmortem AMD subjects. Collectively, our findings reveal an atrophy-associated specialization of microglia that restricts the progression of retinal degeneration in mice and further suggest that these protective microglia are conserved in AMD.

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Section: Augmentation Of Trem2 Activity Ameliorates Retinal Degenerat...supporting

confidence: 93%

Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions

Lad

Mathew

et al. 2023

Preprint

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“…Western blot analysis was described previously ( 59 ). The retinas were dissected and snap-frozen in liquid nitrogen and stored in −80°C until use.…”

Section: Methodsmentioning

confidence: 99%

Modulation of cGAS-STING signaling by PPARα in a mouse model of ischemia-induced retinopathy

Liang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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In ischemic retinopathy, overactivated retinal myeloid cells are a crucial driving force of pathological angiogenesis and inflammation. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling are key regulators of inflammation. This study aims to investigate the association of cGAS-STING signaling with ischemic retinopathy and the regulation of its activation. We found that protein levels of cGAS and STING were markedly up-regulated in retinal myeloid cells isolated from mice with oxygen-induced retinopathy (OIR). Knockout of Sting and pharmacological inhibition of STING both alleviated retinal neovascularization (NV) and reduced retinal vascular leakage in OIR. Further, Sting knockout and STING inhibitor also alleviated leukocyte adhesion to retinal vasculature and infiltration into the retina as well as microglial activation in OIR. These results suggest that cGAS-STING signaling played a pathogenic role in retinal myeloid cell activation and NV in ischemic retinopathy. To identify the regulation of cGAS-STING signaling in OIR, we evaluated the role of transcription factor peroxisome proliferator-activated receptor α (PPARα). The results demonstrated that PPARα was down-regulated in OIR retinas, primarily in myeloid cells. Furthermore, Pparα knockout significantly up-regulated cGAS and STING levels in retinal CD11b + cells, while PPARα agonist inhibited cGAS-STING signaling and cytosolic mitochondrial DNA (mtDNA) release, a causative feature for cGAS activation. Knockout of Sting ameliorated retinal NV, hyperpermeability, and leukostasis in Pparα −/− mice with OIR. These observations suggest that PPARα regulates cGAS-STING signaling, likely through mtDNA release, and thus, is a potential therapeutic target for ischemic retinopathy.

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“…The RPE tissues were homogenized by ultrasonic disruption. For measuring sVLDLR in the IPM of laser‐induced CNV, the IPM were collected from 5 mice (10 eyeballs) per group and combined according to a documented protocol 25,34 . Briefly, the retinas were collected and gently rinsed with PBS containing proteinase inhibitors.…”

Section: Methodsmentioning

confidence: 99%

“…For measuring sVLDLR in the IPM of laser-induced CNV, the IPM were collected from 5 mice (10 eyeballs) per group and combined according to a documented protocol. 25 , 34 Briefly, the retinas were collected and gently rinsed with PBS containing proteinase inhibitors. The PBS was then centrifuged at 1000× g for 5 min to remove cell debris, followed by ultra-centrifugation at 70 000× g for 1 h to remove cell membranes.…”

Section: Methodsmentioning

confidence: 99%

Soluble very low‐density lipoprotein receptor (sVLDLR) inhibits fibrosis in neovascular age‐related macular degeneration

Takahashi

et al. 2021

The FASEB Journal

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Subretinal fibrosis is a key pathological feature in neovascular age‐related macular degeneration (nAMD). Previously, we identified soluble very low‐density lipoprotein receptor (sVLDLR) as an endogenous Wnt signaling inhibitor. This study investigates whether sVLDLR plays an anti‐fibrogenic role in nAMD models, including Vldlr−/− mice and laser‐induced choroidal neovascularization (CNV). We found that fibrosis factors including P‐Smad2/3, α‐SMA, and CTGF were upregulated in the subretinal area of Vldlr−/− mice and the laser‐induced CNV model. The antibody blocking Wnt co‐receptor LRP6 significantly attenuated the overexpression of fibrotic factors in these two models. Moreover, there was a significant reduction of sVLDLR in the interphotoreceptor matrix (IPM) in the laser‐induced CNV model. A transgenic strain (sVLDLR‐Tg) with sVLDLR overexpression in the IPM was generated. Overexpression of sVLDLR ameliorated the profibrotic changes in the subretinal area of the laser‐induced CNV model. In addition, Wnt and TGF‐β signaling synergistically promoted fibrogenesis in human primary retinal pigment epithelium (RPE) cells. CRISPR/Cas9‐mediated LRP6 gene knockout (KO) attenuated this synergistic effect. The disruption of VLDLR expression promoted, while the overexpression of sVLDLR inhibited TGF‐β‐induced fibrosis. These findings suggest that overactivated Wnt signaling enhances the TGF‐β pathway in subretinal fibrosis. sVLDLR confers an antifibrotic effect, at least partially, through the inhibition of Wnt signaling and thus, has therapeutic potential for fibrosis.

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ADAM17 mediates ectodomain shedding of the soluble VLDL receptor fragment in the retinal epithelium

Cited by 8 publications

References 42 publications

Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions

Microglia at Sites of Atrophy Restrict the Progression of Retinal Degeneration via Galectin-3 and Trem2 Interactions

Modulation of cGAS-STING signaling by PPARα in a mouse model of ischemia-induced retinopathy

Soluble very low‐density lipoprotein receptor (sVLDLR) inhibits fibrosis in neovascular age‐related macular degeneration

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