MicroRNA-93/STAT3 signalling pathway mediates retinal microglial activation and protects retinal ganglion cells in an acute ocular hypertension model

Abstract

Glaucoma is a common neurodegenerative disease and a leading cause of irreversible blindness worldwide. Retinal microglia-mediated neuroinflammation is involved in the process of optic nerve damage, but the mechanisms driving this microglial activation remain mostly elusive. Previous investigations reported that microRNAs are associated with the retinal microglial reaction and neural apoptosis. In the present study, we found that microRNA-93-5p (miR-93) played a key role in the reaction of retinal microglial cells in vivo and in vitro. The miR-93 level was significantly reduced in the retinae of rat acute ocular hypertension (AOH) models, which were accompanied by retinal microglial activation, overproduction of inflammatory cytokines, and subsequent retinal ganglion cells (RGCs) death, versus the retinae of controls. The induction of miR-93 overexpression significantly reduced microglial proliferation, migration and cytokine release, inhibited the expression of the target gene signal transducer and activator of transcription 3 (STAT3) and p-STAT3, and was associated with a reduced loss of RGCs. Treatment with a STAT3 inhibitor also decreased retinal microglial activation after AOH injury. Taken together, these results suggest that the miR-93/STAT3 pathway is directly related to the downregulation of retinal microglia-mediated neuro-inflammation and showed a neuroprotective effect. Regulating microglial activation through miR-93 may serve as a target for neuroprotective therapy in pathological ocular hypertension.

Aryl hydrocarbon receptor dependent anti-inflammation and neuroprotective effects of tryptophan metabolites on retinal ischemia/reperfusion injury

“…1D). Similar findings were also showed in mice IR injury, a well-validated model of glaucoma [27,28] (Fig. 1D).…”

“…Here, we postulated a new perspective of supplementing endogenous tryptophan derived AhR ligands to confer neuroprotection in glaucoma. We aimed to modulate the intrinsic changes of tryptophan metabolism and AhR signaling that affect microglia activity to inhibit local inflammation in glaucoma [ 28 , 41 ]. Previous study discussed the role of tryptophan metabolism in POAG, mainly focusing on the association of microglia mediated neurotoxicity [ 36 ].…”

Mi-RNA-93 and Mi-RNA-152 in the Diagnosis of Type 2 Diabetes and Diabetic Retinopathy

“…Fuchs et al ( 30 ) reported the ability of miRNA-93 to suppress TGFβ-induced VEGFA secretion from retinal pigment epithelium cell lines and to convert TGFβ-induced mesenchymal retinal epithelial cells back to the epithelial-like status, which part-explains our finding of a gradual decrease in miRNA-93 expression across patient groups, with the lowest expression level in patients with proliferative diabetic retinopathy. Similarly, miR-93 expression was reduced in acute ocular hypertension retinae compared to controls and miR-93 upregulation suppressed microglial proliferation, inflammation, and cytokine secretion ( 31 ). Moreover, miR-93 was also investigated in diabetic renal vascular complications suggesting its antiangiogenic and antifibrotic properties and showed decreased expression in renal tissue of patients with diabetic nephropathy ( 32 ), and in a diabetic kidney model was speculated to affect nucleosome remodeling ( 10 ).…”

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

“…Melatonin can inhibit microglia activation through the PI3K/Akt/Stat3/NF-κB signal axis and protect pericytes from apoptosis ( Tang L. et al, 2022 ). And MicroRNA-93-5p can restrain M1 microglia activation by silencing STAT3 ( Wang et al, 2021 ).…”