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Research article
Intracellular complement C3/C3aR/STAT3 pathway inactivation attenuates retinal degeneration in mice
Guang-Hua Peng
Zhengzhou University
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3813-6942
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Age-related macular degeneration (AMD) threatens vision in elderly people globally. Systemic complement C3 has been shown to be tightly associated with AMD. However, the mechanism of how local retinal complement C3 and downstream pathway mediated retinal degeneration is not entirely clear.
Methods
Wild-type, C3 knockout mice and mice treated with a C3aR inhibitor (SB290157), STAT3 inhibitor (SH-4-54), were exposed to sodium iodine (NaIO3), respectively. C3 localization in degenerated retina was detected by using immunostaining. Retinal function was assessed by electroretinography, followed by histological analyses to assess RPE and photoreceptor cell degeneration. Retinal inflammation and mitochondrion were investigated through Real-time PCR, ELISA and RNA-Seq.
Results
We reported here that activation of complement was positively associated with retinal degeneration. Strikingly, intracellular C3 was activated in retinal pigment epithelial (RPE) cells, and subsequently promoted the formation of the membrane-attack complex (MAC), which contributed to apoptosis of RPE cells. Intracellular C3 deficiency or pharmalogical inhibition could rescue RPE cells from apoptosis. Moreover, genetic deletion of C3 or inhibition of C3aR/STAT3 results in alleviating immune response and rescue of photoreceptor cells under oxidative stress. Mechanistically, through RNA-Seq, we identified C3/C3aR/STAT3 pathway functionally mediated immune response and photoreceptor cell degeneration.
Conclusions
These results indicate that inhibition of the C3/C3aR/STAT3 pathway might be a new therapeutic intervention for AMD and other retinal degeneration diseases.
Keywords
complement C3, retinal pigment epithelium, retinal degeneration, membrane-attack-complex, apoptosis, age-related macular degeneration
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This is a preprint. It has not completed peer review.
Research article
Intracellular complement C3/C3aR/STAT3 pathway inactivation attenuates retinal degeneration in mice
Guang-Hua Peng
Zhengzhou University
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3813-6942
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 22 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Age-related macular degeneration (AMD) threatens vision in elderly people globally. Systemic complement C3 has been shown to be tightly associated with AMD. However, the mechanism of how local retinal complement C3 and downstream pathway mediated retinal degeneration is not entirely clear.
Methods
Wild-type, C3 knockout mice and mice treated with a C3aR inhibitor (SB290157), STAT3 inhibitor (SH-4-54), were exposed to sodium iodine (NaIO3), respectively. C3 localization in degenerated retina was detected by using immunostaining. Retinal function was assessed by electroretinography, followed by histological analyses to assess RPE and photoreceptor cell degeneration. Retinal inflammation and mitochondrion were investigated through Real-time PCR, ELISA and RNA-Seq.
Results
We reported here that activation of complement was positively associated with retinal degeneration. Strikingly, intracellular C3 was activated in retinal pigment epithelial (RPE) cells, and subsequently promoted the formation of the membrane-attack complex (MAC), which contributed to apoptosis of RPE cells. Intracellular C3 deficiency or pharmalogical inhibition could rescue RPE cells from apoptosis. Moreover, genetic deletion of C3 or inhibition of C3aR/STAT3 results in alleviating immune response and rescue of photoreceptor cells under oxidative stress. Mechanistically, through RNA-Seq, we identified C3/C3aR/STAT3 pathway functionally mediated immune response and photoreceptor cell degeneration.
Conclusions
These results indicate that inhibition of the C3/C3aR/STAT3 pathway might be a new therapeutic intervention for AMD and other retinal degeneration diseases.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9