Attenuated glial reactions and photoreceptor degeneration after retinal detachment in mice deficient in glial fibrillary acidic protein and vimentin.
OBJECTIVE
To characterize the reactions of retinal glial cells (astrocytes and Müller cells) to retinal injury in mice that lack glial fibrillary acidic protein (GFAP) and vimentin (GFAP-/-Vim-/-) and to determine the role of glial cells in retinal detachment (RD)-induced photoreceptor degeneration.


METHODS
RD was induced by subretinal injection of sodium hyaluronate in adult wild-type (WT) and GFAP-/-Vim-/- mice. Astroglial reaction and subsequent monocyte recruitment were quantified by measuring extracellular signal-regulated kinase (Erk) and c-fos activation and the level of expression of chemokine monocyte chemoattractant protein (MCP)-1 and by counting monocytes/microglia in the detached retinas. Immunohistochemistry, immunoblotting, real-time quantitative polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) were used. RD-induced photoreceptor degeneration was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and measurement of outer nuclear layer (ONL) thickness.


RESULTS
RD-induced reactive gliosis, characterized by GFAP and vimentin upregulation, Erk and c-fos activation, MCP-1 induction, and increased monocyte recruitment in WT mice. Absence of GFAP and vimentin effectively attenuated reactive responses of retinal glial cells and monocyte infiltration. As a result, detached retinas of GFAP-/-Vim-/- mice exhibited significantly reduced numbers of TUNEL-positive photoreceptor cells and increased ONL thickness compared with those of WT mice.


CONCLUSIONS
The absence of GFAP and vimentin attenuates RD-induced reactive gliosis and, subsequently, limits photoreceptor degeneration. Results of this study indicate that reactive retinal glial cells contribute critically to retinal damage induced by RD and provide a new avenue for limiting photoreceptor degeneration associated with RD and other retinal diseases or damage.
Nakazawa
Toru
T
Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
Takeda
Masumi
M
Lewis
Geoffrey P
GP
Cho
Kin-Sang
KS
Jiao
Jianwei
J
Wilhelmsson
Ulrika
U
Fisher
Steven K
SK
Pekny
Milos
M
Chen
Dong F
DF
Miller
Joan W
JW
D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000172:deficiency / Q000502:physiology*; D005911:Gliosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D009000:Monocytes / Q000502:physiology; D009457:Neuroglia / Q000502:physiology*; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012160:Retina / Q000473:pathology*; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D012163:Retinal Detachment / Q000150:complications*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014746:Vimentin / Q000172:deficiency / Q000502:physiology*
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; D016760:Proto-Oncogene Proteins c-fos; D014746:Vimentin; D048049:Extracellular Signal-Regulated MAP Kinases