title: Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration.
abstract: OBJECTIVE
  Senescent Ccl2(-/-) mice are reported to develop cardinal features of human age-related macular degeneration (AMD). Loss-of-function single-nucleotide polymorphisms within CX3CR1 are also found to be associated with AMD. The authors generated Ccl2(-/-)/Cx3cr1(-/-) mice to establish a more characteristic and reproducible AMD model.
  
  
  METHODS
  Single Ccl2- and Cx3cr1-deficient mice were crossbred to obtain Ccl2(-/-)/Cx3cr1(-/-) mice. Funduscopy, histopathology, retinal A2E quantification, proteomics, RT-PCR gene expression assay, immunochemistry, and Western blotting were used to examine the retina and to evaluate gene expression within the retinal tissue.
  
  
  RESULTS
  By 6 weeks of age, all Ccl2(-/-)/Cx3cr1(-/-) mice developed AMD-like retinal lesions, including drusen, retinal pigment epithelium alteration, and photoreceptor degeneration. Furthermore, choroidal neovascularization occurred in 15% of the mice. These degenerative lesions progressed with age. A2E, a major lipofuscin fluorophore that accumulated during AMD progression, was significantly higher in the Ccl2(-/-)/Cx3cr1(-/-) retina than in the wild-type retina. Complement cofactor was higher in the Ccl2(-/-)/Cx3cr1(-/-) RPE. Proteomics data indicated that four proteins were differentially expressed in Ccl2(-/-)/Cx3cr1(-/-) retina compared with control. One of these proteins, ERp29, an endoplasmic reticulum protein, functions as an escort chaperone and in protein folding.
  
  
  CONCLUSIONS
  The authors concluded that Ccl2(-/-)/Cx3cr1(-/-) mice develop a broad spectrum of AMD abnormalities with early onset and high penetrance. These observations implicate certain chemokines and endoplasmic reticulum proteins in AMD pathogenesis. Similar to the mechanism of neurodegeneration caused by dysfunction of endoplasmic reticulum proteins, decreased chaperoning may cause misfolded protein accumulation, leading to drusen formation and retinal degeneration.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1857, USA.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tuo
authors.forename: Christine M
authors.initials: CM
authors.lastname: Bojanowski
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Defen
authors.initials: D
authors.lastname: Shen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ross
authors.forename: Kevin I
authors.initials: KI
authors.lastname: Rosenberg
authors.forename: D Joshua
authors.initials: DJ
authors.lastname: Cameron
authors.forename: Chunyue
authors.initials: C
authors.lastname: Yin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kowalak
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D011726:Pyridinium Compounds / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000473:pathology / Q000648:ultrastructure; D015593:Retinal Drusen / Q000235:genetics / Q000473:pathology; D012176:Retinoids / Q000378:metabolism
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); D000073883:CX3C Chemokine Receptor 1; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C471885:Cx3cr1 protein, mouse; C491738:ERP29 protein, human; C491737:Erp29 protein, mouse; D006360:Heat-Shock Proteins; D011726:Pyridinium Compounds; D019707:Receptors, Chemokine; D012176:Retinoids; D003179:Complement C3b; D015935:Complement C4b