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Deficiency of CC chemokine ligand 2 and decay-accelerating factor causes retinal degeneration in mice
Minzhong Yu1, Kai Kang2, Ping Bu3
1Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
Insights
Loss of CC chemokine ligand 2 (CCL2) and decay-accelerating factor (DAF) causes retinal degeneration. This is linked to increased endoplasmic reticulum stress, oxidative stress, and inflammation in the retina.
Area of Science:
- Ophthalmology
- Immunology
- Neuroscience
Background:
- CC chemokine ligand 2 (CCL2) is crucial for macrophage recruitment in inflammatory responses.
- Decay-accelerating factor (DAF) regulates complement system activation.
- Complement system genes are implicated in retinal diseases.
Purpose of the Study:
- To evaluate the retinal phenotype of mice lacking Ccl2 and/or Daf1.
- To investigate the role of Ccl2 and Daf1 in retinal degeneration.
Main Methods:
- Phenotypic analysis of C57BL/6J, Ccl2(-/-), Daf1(-/-), and Ccl2(-/-)/Daf1(-/-) mice at 12 months.
- Utilized scanning laser ophthalmoscopy, electroretinography (ERG), histology, immunohistochemistry, and TUNEL assay.
- Assessed levels of endoplasmic reticulum stress markers (GPR78, ATF4) and signaling pathways (NF-κB, p38, ERK, JNK, SIRT1).
Main Results:
- Ccl2(-/-)/Daf1(-/-) mice exhibited increased autofluorescent foci and significant reduction in ERG amplitudes.
- TUNEL-positive cells and neuronal cell loss were prevalent in Ccl2(-/-)/Daf1(-/-) retinas, particularly in nuclear layers.
- Elevated endoplasmic reticulum stress markers, increased inflammatory signaling (NF-κB, p38, ERK, JNK), and decreased SIRT1 were observed in Ccl2(-/-)/Daf1(-/-) retinas.
Conclusions:
- Combined loss of Ccl2 and Daf1 leads to significant retinal neuronal death and degeneration.
- Retinal degeneration is associated with exacerbated endoplasmic reticulum stress, oxidative stress, and inflammation.
- These findings highlight the critical roles of CCL2 and DAF in maintaining retinal health.
Abstract:
CC chemokine ligand 2 (CCL2) recruits macrophages to reduce inflammatory responses. Decay-accelerating factor (DAF) is a membrane regulator of the classical and alternative pathways of complement activation. In view of the link between complement genes and retinal diseases, we evaluated the retinal phenotype of C57BL/6J mice and mice lacking Ccl2 and/or Daf1 at 12 months of age, using scanning laser ophthalmoscopic imaging, electroretinography (ERG), histology, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. In comparison to C57BL/6J mice, mutant mice had an increased number of autofluorescent foci, with the greatest number in the Ccl2(-/-)/Daf1(-/-) retina. ERG amplitudes in Ccl2(-/-)/Daf1(-/-), Ccl2(-/-) and Daf1(-/-) mice were reduced, with the greatest reduction in Ccl2(-/-)/Daf1(-/-) mice. TUNEL-positive cells were not seen in C57BL/6J retina, but were prevalent in the outer and inner nuclear layers of Ccl2(-/-)Daf1(-/-) mice and were present at reduced density in Ccl2(-/-) or Daf1(-/-) mice. Cell loss was most pronounced in the outer and inner nuclear layers of Ccl2(-/-)/Daf1(-/-) mice. The levels of the endoplasmic reticulum chaperone GPR78 and transcription factor ATF4 were significantly increased in the Ccl2(-/-)/Daf1(-/-) retina. In comparison to the C57BL/6J retina, the phosphorylation of NF-κB p65, p38, ERK and JNK was significantly upregulated while SIRT1 was significantly downregulated in the Ccl2(-/-)/Daf1(-/-) retina. Our results suggest that loss of Ccl2 and Daf1 causes retinal neuronal death and degeneration which is related to increased endoplasmic reticulum stress, oxidative stress and inflammation.
