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

Abstract

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.

The Alarmin Effect of Hmgb1/Rip3 on Transfusion-Related Acute Lung Injury via Tlr4/Nf-Κb or Mapk Pathway

“…Necrosis can result in cell membrane rupture and cell content release, such as HMGB1, which can be more proinflammatory than apoptosis ( 18 ). On the other hand, RIP3 can induce necroptosis and the production of multiple cytokines, thereby participating in the inflammatory response of related diseases ( 19 ). The mRNA and protein expression levels of HMGB1 and RIP3 were analyzed in TRALI rat lungs to explore the relationship between inflammation and HMGB1/RIP3 in TRALI.…”

Peroxynitrite reduces Treg cell expansion and function by mediating IL-2R nitration and aggravates multiple sclerosis pathogenesis

“…Excessive oxidative stress in the CNS can lead to neuronal damage [ 34 , 35 , [63] , [64] , [65] ]. Interestingly, primarily peripheral redox imbalance can also induce neuroinflammation and nerve damage, resulting in neuropathic pain in diabetes [ 66 , 67 ]. In the present study, we demonstrated that peroxynitrite could be a critical player in disrupting the ratio of Treg/Th17 in the peripheral immune system and aggravating neuroinflammation and neurological deficit in active EAE/MS pathogenesis.…”

Role of myeloid cells in ischemic retinopathies: recent advances and unanswered questions

“…The microglia-mediated inflammatory response can be attenuated pharmacologically by drugs such as minocycline [ 117 ]. A recent report showed that microglia undergo necroptosis in DR secondary to hyperglycemia [ 118 ]. In this study, the authors used a pharmacological inhibitor of necroptosis and concluded that inhibiting necroptosis of microglia ameliorated retinal neuroinflammation and neurodegeneration, thereby suggesting a protective role of the microglia.…”