Therapeutic Benefit of Melatonin in Choroidal Neovascularization During Aging Through the Regulation of Senescent Macrophage/Microglia Polarization

Abstract

Purpose This study aimed to investigate the age-dependent anti-angiogenic capability of melatonin in choroidal neovascularization (CNV) and to explore the underlying molecular mechanisms. Methods In the present study, a laser-induced CNV model was established in both young (three months of age) and old (18 months of age) mice, and the size of CNV lesions and vascular leakage was detected by morphological and imaging examination. Next, Western blot and immunostaining were used to observe the levels of M2 markers, senescence-related markers, and molecules involved in IL-10/STAT3 pathway. Additionally, colivelin was used to study the effect of IL-10/STAT3 pathway activation on the expression of M2 markers and senescence-related markers by Western blot and immunostaining. Finally, the effects of colivelin on melatonin-induced reduction of CNV size and vascular leakage in mice at different ages were assessed using morphological and imaging examination. Results Our results revealed that aging promoted M2 macrophage/microglia polarization, and aggravated CNV and vascular leakage. Melatonin significantly inhibited the M2 polarization of senescent macrophage/microglia and reduced the CNV area and vascular leakage. Moreover, melatonin markedly suppressed IL-10/STAT3 pathway activation in the macrophage/microglia of old mice, and STAT3 activator colivelin reversed the suppressive effect of melatonin on M2 polarization of senescent macrophage/microglia and laser-induced CNV in old mice. Conclusions Our data demonstrated that melatonin significantly prevented the M2 polarization of senescent macrophage/microglia by inhibiting the IL-10/STAT3 pathway, and eventually attenuated senescence-associated CNV. These findings suggested that melatonin could serve as a promising therapeutic agent to treat CNV and other age-related ocular diseases.

Microglial repopulation restricts ocular inflammation and choroidal neovascularization in mice

“…In addition, microglial repopulation reduced lipofuscin deposition, restored aging characteristics and improved cognition in the aging brain ( 49 , 50 ). Consistent with several previous studies ( 42 , 43 ), our results showed that cellular senescence characteristics exist in CNV lesions. However, microglial repopulation significantly enhanced microglial phagocytic function and inhibited cellular senescence and reduced CNV size in the laser-induced CNV model, suggesting microglial repopulation as an effective antiaging option for senescence-associated CNV.…”

“…Although advanced age is the most well-documented risk factor for AMD ( 1 , 3 ), the ways in which aging impacts AMD progression and how to suppress this influence remain incompletely understood. Notably, previous studies have demonstrated that senescent cells are abundant in human eyes with AMD ( 42 , 43 ). Accumulating evidence indicates that senescent cells may directly and indirectly damage the local microenvironment, which disrupts the maintenance of retinal homeostasis and exacerbates retinal degeneration ( 44 – 46 ).…”

Aging in Ocular Blood Vessels: Molecular Insights and the Role of Oxidative Stress

“…The impact of aging on the retina and choroid is particularly pronounced, with retinal aging, especially in the macular area of the central retina, posing a significant clinical concern. Age-related macular degeneration (AMD) stands as a leading cause of blindness among older adults, with an expected increase in patients to 288 million by 2040 [6]. Furthermore, advanced age emerges as a major risk factor for retinal vascular occlusion and immunological diseases that may affect the ocular vasculature, such as giant cell arteritis [3].…”