Deficiency of CC chemokine ligand 2 and decay-accelerating factor causes retinal degeneration in mice.

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.

• Authors: Minzhong Yu, Kai Kang, Ping Bu, Brent A Bell, Charles Kaul, James B Qiao, Gwen Sturgill-Short, Xiaoshan Yu, Matthew J Tarchick, Craig Beight, Sarah X Zhang, Neal S Peachey
• Journal: Experimental eye research (Exp Eye Res) Vol. 138 Pg. 126-33 (Sep 2015) ISSN: 1096-0007 [Electronic] England
• PMID: 26149093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Atf4 protein, mouse
• CD55 Antigens
• Ccl2 protein, mouse
• Chemokine CCL2
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• Hspa5 protein, mouse
• NF-kappa B
• decay-accelerating factor 1, mouse
• Activating Transcription Factor 4
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Activating Transcription Factor 4 (metabolism)
• Animals
• Apoptosis
• CD55 Antigens (physiology)
• Chemokine CCL2 (physiology)
• Disease Models, Animal
• Electroretinography
• Endoplasmic Reticulum Chaperone BiP
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Heat-Shock Proteins (metabolism)
• Immunohistochemistry
• In Situ Nick-End Labeling
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Retinal Degeneration (etiology, metabolism, physiopathology)
• Retinal Neurons (pathology)
• p38 Mitogen-Activated Protein Kinases (metabolism)