title: 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.affiliation: Department 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. Electronic address: yum@ccf.org.
authors.forename: Minzhong
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Bu
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Bell
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kaul
authors.affiliation: Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Qiao
authors.affiliation: Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA.
authors.forename: Gwen
authors.initials: G
authors.lastname: Sturgill-Short
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tarchick
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Beight
authors.affiliation: Departments of Ophthalmology and Biochemistry, SUNY-Buffalo and SUNY Eye Institute, Buffalo, NY, USA.
authors.forename: Sarah X
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: Department 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; Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D018958:CD55 Antigens / Q000502:physiology*; D018932:Chemokine CCL2 / Q000502:physiology*; D004195:Disease Models, Animal; D004596:Electroretinography; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D012162:Retinal Degeneration / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D055351:Retinal Neurons / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C081452:Atf4 protein, mouse; D018958:CD55 Antigens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D016328:NF-kappa B; C521184:decay-accelerating factor 1, mouse; D051701:Activating Transcription Factor 4; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Apoptosis; CC chemokine ligand 2; Decay accelerating factor; Endoplasmic reticulum stress; Oxidative stress; Retinal degeneration