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AICAR suppresses TNF-α-induced complement factor B in RPE cells.
Eun Jee Chung1,2, Nikolaos E Efstathiou1, Eleni K Konstantinou1
1Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, 02114, United States.
Scientific Reports
|December 17, 2017
Summary
AICAR, a potential therapeutic, inhibits complement factor B (CFB) in retinal pigment epithelium (RPE) cells. This effect occurs independently of AMP-dependent kinase (AMPK) activation, offering new avenues for treating complement-related eye diseases.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss.
- Retinal pigment epithelium (RPE) dysfunction and complement dysregulation are implicated in AMD pathogenesis.
- Tumor necrosis factor alpha (TNF-α) can induce complement factor B (CFB) expression in RPE cells.
Purpose of the Study:
- To investigate the effect of AICAR, an AMP-dependent kinase (AMPK) activator, on TNF-α-induced CFB expression in RPE cells.
- To determine if the effects of AICAR are mediated through AMPK activation.
Main Methods:
- ARPE-19 and primary human RPE cells were treated with TNF-α and AICAR.
- Dipyridamole was used to block AICAR uptake, and 5-iodotubericidin inhibited AICAR conversion to its active form.
- AMPK knockout in RPE cells was achieved using CRISPR/Cas9 technology.
Main Results:
- AICAR significantly inhibited TNF-α-induced CFB expression in RPE cells in a dose-dependent manner.
- Inhibition of AICAR uptake or its conversion to the active AMPK activator abolished AICAR's effects.
- AMPK knockout RPE cells still exhibited AICAR-mediated inhibition of CFB expression, indicating an AMPK-independent mechanism.
Conclusions:
- AICAR suppresses TNF-α-induced CFB expression in RPE cells via an AMPK-independent pathway.
- These findings suggest AICAR as a potential therapeutic agent for conditions involving complement over-activation in the eye.
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