In glaucoma the upregulated truncated TrkC.T1 receptor isoform in glia causes increased TNF-alpha production, leading to retinal ganglion cell death.
OBJECTIVE
Glaucoma is a distinct neuropathy characterized by the chronic and progressive death of retinal ganglion cells (RGCs). The etiology of RGC death remains unknown. Risk factors for glaucomatous RGC death are elevated intraocular pressure and glial production of tumor necrosis factor-alpha (TNF-α). Previously, the authors showed that glaucoma causes a rapid upregulation of a neurotrophin receptor truncated isoform lacking the kinase domain, TrkC.T1, in retina. Here they examined the biological role of TrkC.T1 during glaucoma progression.


METHODS
Rat and mouse models of chronic ocular hypertension were used. Immunofluorescence Western blot analysis and in situ mRNA hybridization were used to identify cells upregulating TrkC.T1. A genetic model of engineered mice lacking TrkC.T1 (TrkC.T1(-/-)) was used to validate a role for this receptor in glaucoma. Pharmacologic studies were conducted to evaluate intravitreal delivery of agonists or antagonists of TrkC.T1, compared with controls, during glaucoma. Surviving RGCs were quantified by retrograde-labeling techniques. Production of neurotoxic TNF-α and α2 macroglobulin were quantified.


RESULTS
TrkC.T1 was upregulated in retinal glia, with a pattern similar to that of TNF-α. TrkC.T1(-/-) mice had normal retinas. However, during experimental glaucoma, TrkC.T1(-/-) mice had lower rates of RGC death and produced less TNF-α than wild-type littermates. In rats with glaucoma, the pharmacologic use of TrkC antagonists delayed RGC death and reduced the production of retinal TNF-α.


CONCLUSIONS
TrkC.T1 is implicated in glaucomatous RGC death through the control of glial TNF-α production. Overall, the data point to a paracrine mechanism whereby elevated intraocular pressure upregulated glial TrkC.T1 expression in glia; TrkC.T1 controlled glial TNF-α production, and TNF-α caused RGC death.
Bai
Yujing
Y
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Shi
ZhiHua
Z
Zhuo
Yehong
Y
Liu
Jing
J
Malakhov
Andrey
A
Ko
Eunhwa
E
Burgess
Kevin
K
Schaefer
Henry
H
Esteban
Pedro F
PF
Tessarollo
Lino
L
Saragovi
H Uri
HU
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D004195:Disease Models, Animal; D018274:Electroporation; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005822:Genetic Vectors; D005901:Glaucoma / Q000378:metabolism*; D017403:In Situ Hybridization; D007429:Intraocular Pressure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism*; D020033:Protein Isoforms / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020812:Receptor, trkC / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D000511:alpha-Macroglobulins / Q000378:metabolism
D020033:Protein Isoforms; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000511:alpha-Macroglobulins; D020812:Receptor, trkC