Abstract
Subretinal fibrosis is directly related to severe visual loss, especially if occurs in the macula, and is frequently observed in advanced age-related macular degeneration and other refractory eye disorders such as diabetic retinopathy and uveitis. In this study, we analyzed the immunosuppressive mechanism of subretinal fibrosis using the novel animal model recently demonstrated. Both TLR2 and TLR4 deficient mice showed significant enlargement of subretinal fibrotic area as compared with wild-type mice. A single intraocular administration of heat shock protein 70 (HSP70), which is an endogenous ligand for TLR2 and TLR4, inhibited subretinal fibrosis in wild-type mice but not in TLR2 and TLR4-deficient mice. Additionally, HSP70 induced IL-10 production in eyes from wild-type mice but was impaired in both TLR2- and TLR4-deficient mice, indicating that HSP70-TLR2/TLR4 axis plays an immunomodulatory role in subretinal fibrosis. Thus, these results suggest that HSP70-TLR2/TLR4 axis is a new therapeutic target for subretinal fibrosis due to prognostic CNV.
Highlights
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness, which is estimated to affect more than 8 million individuals in the USA, and the advanced form of the disease affects more than 1.75 million individuals [1]
We show the importance of heat shock protein 70 (HSP70) in subretinal formation by inducing immunomodulatory cytokine IL-10
The anti-inflammatory properties of heat shock proteins (HSP) have been shown in several studies in both animal models and in patients suffering from inflammatory diseases [16]
Summary
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness, which is estimated to affect more than 8 million individuals in the USA, and the advanced form of the disease affects more than 1.75 million individuals [1]. The neovascular form of the disease is characterized by the invasion of new pathological vessels under the macula (choroidal neovascularization, CNV) and it is associated with a rapid and severe decrease of vision. Numerous studies about the mechanism of CNV formation have been reported, many of which resulted in the initiation of clinical trials. Little is known regarding the molecular mechanism(s) of tissue scar formation in CNV. Since fibrotic changes in the foveal CNV lesion frequently result in severe, permanent visual impairment in patients with wet AMD, the treatment of tissue fibrosis in the late stage of AMD is of great interest
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