Hypoxia Inhibits Subretinal Inflammation Resolution Thrombospondin-1 Dependently
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Published on: September 16, 2020
Sara Touhami1,2, Fanny Béguier1, Tianxiang Yang1
1Institut de la Vision, Sorbonne Université, INSERM, CNRS, 75012 Paris, France.
Abstract:
Hypoxia is potentially one of the essential triggers in the pathogenesis of wet age-related macular degeneration (wetAMD), characterized by choroidal neovascularization (CNV) which is driven by the accumulation of subretinal mononuclear phagocytes (MP) that include monocyte-derived cells. Here we show that systemic hypoxia (10% O2) increased subretinal MP infiltration and inhibited inflammation resolution after laser-induced subretinal injury in vivo. Accordingly, hypoxic (2% O2) human monocytes (Mo) resisted elimination by RPE cells in co-culture. In Mos from hypoxic mice, Thrombospondin 1 mRNA (Thbs1) was most downregulated compared to normoxic animals and hypoxia repressed Thbs-1 expression in human monocytes in vitro. Hypoxic ambient air inhibited MP clearance during the resolution phase of laser-injury in wildtype animals, but had no effect on the exaggerated subretinal MP infiltration observed in normoxic Thbs1-/--mice. Recombinant Thrombospondin 1 protein (TSP-1) completely reversed the pathogenic effect of hypoxia in Thbs1-/--mice, and accelerated inflammation resolution and inhibited CNV in wildtype mice. Together, our results demonstrate that systemic hypoxia disturbs TSP-1-dependent subretinal immune suppression and promotes pathogenic subretinal inflammation and can be therapeutically countered by local recombinant TSP-1.
Insights
Systemic hypoxia worsens wet age-related macular degeneration (wetAMD) by increasing subretinal immune cells and reducing inflammation resolution. Thrombospondin-1 (TSP-1) therapy counteracts these effects, offering a potential treatment for wetAMD.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Wet age-related macular degeneration (wetAMD) pathogenesis involves choroidal neovascularization (CNV).
- Subretinal mononuclear phagocytes (MPs), including monocyte-derived cells, accumulate in wetAMD.
- Hypoxia is a potential trigger for wetAMD development.
Purpose of the Study:
- To investigate the role of hypoxia in subretinal MP infiltration and inflammation resolution.
- To explore the impact of hypoxia on Thrombospondin-1 (TSP-1) expression in monocytes.
- To evaluate TSP-1 as a therapeutic agent against hypoxia-induced pathogenic inflammation in wetAMD.
Main Methods:
- Laser-induced subretinal injury model in wildtype and Thbs1-/- mice.
- In vivo and in vitro experiments exposing monocytes and animals to hypoxic conditions (10% or 2% O2).
- Analysis of subretinal MP infiltration, inflammation resolution, and TSP-1 expression (mRNA and protein).
Main Results:
- Systemic hypoxia increased subretinal MP infiltration and delayed inflammation resolution post-injury.
- Hypoxic human monocytes resisted elimination by RPE cells; TSP-1 mRNA was downregulated in hypoxic monocytes.
- Recombinant TSP-1 reversed hypoxia's pathogenic effects in Thbs1-/- mice and inhibited CNV in wildtype mice.
Conclusions:
- Systemic hypoxia promotes pathogenic subretinal inflammation by disrupting TSP-1-dependent immune suppression.
- Hypoxia exacerbates wetAMD pathogenesis through altered MP behavior and reduced inflammation resolution.
- Local recombinant TSP-1 administration is a potential therapeutic strategy for wetAMD by counteracting hypoxia's effects.
