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Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

Hypoxia Inhibits Subretinal Inflammation Resolution Thrombospondin-1 Dependently

Résumé

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
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Origine : Publication financée par une institution

Dates et versions

hal-03542967 , version 1 (25-01-2022)

Identifiants

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Sara Touhami, Fanny Béguier, Tianxiang Yang, Sébastien Augustin, Christophe Roubeix, et al.. Hypoxia Inhibits Subretinal Inflammation Resolution Thrombospondin-1 Dependently. International Journal of Molecular Sciences, 2022, 23 (2), pp.681. ⟨10.3390/ijms23020681⟩. ⟨hal-03542967⟩
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