Hypoxia inhibits subretinal inflammation resolution in age related macular degeneration
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Purpose
To investigate the effects of chronic hypoxia on subretinal inflammation in age related macular degeneration (AMD)
Methods
In vivo mice model (C57bl6) of laser induced choroidal neovascularisation (CNV).In vitro coculture of porcine retinal pigment epithelium (RPE) cells and human primary monocytes (Mo)
Results
Exposure of mice to ambient 10%O2 hypoxia increased subretinal MP infiltration and inhibited inflammation resolution after laser-induced subretinal injury,compared to mice kept in room-air.In vitro, hypoxia (2%) delayed the elimination of human Mo in coculture with immunosuppressive RPE, which was also observed in cocultures when Mo,but not RPE cells,were pre-incubated in hypoxia.In vivo,10% hypoxia sufficed to decrease Thrombospondin(TSP)1 and increase Cfh-mRNA expression in Mo that participate in the subretinal inflammation.Contrary to WT animals,hypoxic ambient air during the resolution phase of laser-injury had no effect on the exaggerated subretinal MP infiltration observed in normoxic Thbs1-/-mice and diminished MP accumulation in normoxic Cfh-/-mice.Intravitreal injections of a CFH blocking antibody or recombinant TSP1 reversed the pathogenic effect of hypoxia,accelerated inflammation resolution and inhibited CNV in WT mice
Conclusion
Our results demonstrate that systemic hypoxia disturbs TSP-1 dependent subretinal immune suppression and promotes pathogenic subretinal inflammation.The pathogenic effect of systemic hypoxia can be therapeutically countered by local recombinant TSP1 or CFH inhibition, providing new treatment options for AMD patients
Conflict of interest
No
Author 1
Last name
TOUHAMI
Initials of first name(s)
S
City
PARIS
Country
France
Author 2
Last name
BEGUIER
Initials of first name(s)
F
City
PARIS
Country
France
Author 3
Last name
AUGUSTIN
Initials of first name(s)
S
City
PARIS
Country
France
Author 4
Last name
CHARLES MESSANCE
Initials of first name(s)
H
City
PARIS
Country
France
Author 5
Last name
BODAGHI
Initials of first name(s)
B
City
PARIS
Country
France
Author 6
Last name
GUILLONNEAU
Initials of first name(s)
X
City
PARIS
Country
France
Author 7
Last name
SENNLAUB
Initials of first name(s)
F
City
PARIS
Country
France
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