Protective effects of nattokinase against microvasculopathy and neuroinflammation in diabetic retinopathy.

AIMS: Diabetic retinopathy (DR) is a significant global public health concern. Alternative, safe, and cost-effective pharmacologic approaches are warranted. We aimed to investigate the therapeutic potential of nattokinase (NK) for early DR and the underlying molecular mechanism. METHODS: A mouse model of diabetes induced by streptozotocin was utilized and NK was administered via intravitreal injection. Microvascular abnormities were evaluated by examining the leakage from blood-retinal barrier dysfunction and loss of pericytes. Retinal neuroinflammation was examined through the assessment of glial activation and leukostasis. The level of high mobility group box 1 (HMGB1) and its downstream signaling molecules was evaluated following NK treatment. RESULTS: NK administration significantly improved the blood-retinal barrier function and rescued pericyte loss in the diabetic retinas. Additionally, NK treatment inhibited diabetes-induced gliosis and inflammatory response and protected retinal neurons from diabetes-induced injury. NK also improved high glucose-induced dysfunction in cultured human retinal micrangium endothelial cells. Mechanistically, NK regulated diabetes-induced inflammation partially by modulating HMGB1 signaling in the activated microglia. CONCLUSIONS: This study demonstrated the protective effects of NK against microvascular damages and neuroinflammation in the streptozotocin-induced DR model, suggesting that NK could be a potential pharmaceutical agent for the treatment of DR.

RIP3-mediated microglial necroptosis promotes neuroinflammation and neurodegeneration in the early stages of diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness that poses significant public health concerns worldwide. Increasing evidence suggests that neuroinflammation plays a key role in the early stages of DR. Microglia, long-lived immune cells in the central nervous system, can become activated in response to pathological insults and contribute to retinal neuroinflammation. However, the molecular mechanisms of microglial activation during the early stages of DR are not fully understood. In this study, we used in vivo and in vitro assays to investigate the role of microglial activation in the early pathogenesis of DR. We found that activated microglia triggered an inflammatory cascade through a process called necroptosis, a newly discovered pathway of regulated cell death. In the diabetic retina, key components of the necroptotic machinery, including RIP1, RIP3, and MLKL, were highly expressed and mainly localized in activated microglia. Knockdown of RIP3 in DR mice reduced microglial necroptosis and decreased pro-inflammatory cytokines. Additionally, blocking necroptosis with the specific inhibitor GSK-872 improved retinal neuroinflammation and neurodegeneration, as well as visual function in diabetic mice. RIP3-mediated necroptosis was activated and contributed to inflammation in BV2 microglia under hyperglycaemic conditions. Our data demonstrate the importance of microglial necroptosis in retinal neuroinflammation related to diabetes and suggest that targeting necroptosis in microglia may be a promising therapeutic strategy for the early stages of DR.