A Chimeric Cfh Transgene Leads to Increased Retinal Oxidative Stress, Inflammation, and Accumulation of Activated Subretinal Microglia in Mice
| Autor: | Tao Li, Cynthia Wang, Rafael Ufret-Vincenty, Kaiyan Zhang, Biren Zhao, Bogale Aredo, Xiao Chen, Yu-Guang He, Darlene Gou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Aging Transgene Antigens Differentiation Myelomonocytic Inflammation Mice Transgenic Retinal Pigment Epithelium Biology medicine.disease_cause Retina Mice Antigens CD NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Receptors Immunologic Retinal pigment epithelium Membrane Glycoproteins Microglia eye diseases Cell biology Chemokine CXCL10 Mice Inbred C57BL Disease Models Animal Oxidative Stress medicine.anatomical_structure Factor H Complement Factor H Immunology sense organs medicine.symptom Carrier Proteins Oxidative stress |
| Popis: | 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).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.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.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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|