title: A chimeric Cfh transgene leads to increased retinal oxidative stress, inflammation, and accumulation of activated subretinal microglia in mice.
abstract: OBJECTIVE
  Variants of complement factor H (Cfh) affecting short consensus repeats (SCRs) 6 to 8 increase the risk of age-related macular degeneration. Our aim was to explore the effect of expressing a Cfh variant on the in vivo susceptibility of the retina and RPE to oxidative stress and inflammation, using chimeric Cfh transgenic mice (chCfhTg).
  
  
  METHODS
  The chCfhTg and age-matched C57BL/6J (B6) mice were subjected to oxidative stress by either normal aging, or by exposure to a combination of oral hydroquinone (0.8% HQ) and increased light. Eyes were collected for immunohistochemistry of RPE-choroid flat mounts and of retinal sections, ELISA, electron microscopy, and RPE/microglia gene expression analysis.
  
  
  RESULTS
  Aging mice to 2 years led to an increased accumulation of basal laminar deposits, subretinal microglia/macrophages (MG/MΦ) staining for CD16 and for malondialdehyde (MDA), and MDA-modified proteins in the retina in chCfhTg compared to B6 mice. The chCfhTg mice maintained on HQ diet and increased light showed greater deposition of basal laminar deposits, more accumulation of fundus spots suggestive of MG/MΦ, and increased deposition of C3d in the sub-RPE space, compared to controls. In addition, chCfhTg mice demonstrated upregulation of NLRP3, IP-10, CD68, and TREM-2 in the RNA isolates from RPE/MG/MΦ.
  
  
  CONCLUSIONS
  Expression of a Cfh transgene introducing a variant in SCRs 6 to 8 was sufficient to lead to increased retinal/RPE susceptibility to oxidative stress, a proinflammatory MG/MΦ phenotype, and a proinflammatory RPE/MG/MΦ gene expression profile in a transgenic mouse model. Our data suggest that altered interactions of Cfh with MDA-modified proteins may be relevant in explaining the effects of the Cfh variant.
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Bogale
authors.initials: B
authors.lastname: Aredo
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States 2Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Kaiyan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Cynthia Xin-Zhao
authors.initials: CX
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Darlene
authors.initials: D
authors.lastname: Gou
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Biren
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Ophthalmology UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Ufret-Vincenty
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002352:Carrier Proteins; D054357:Chemokine CXCL10; D017242:Complement Factor H; D008562:Membrane Glycoproteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011971:Receptors, Immunologic; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C485433:Cxcl10 protein, mouse; C492716:Nlrp3 protein, mouse; C498716:Trem2 protein, mouse