Diabetic retinopathy (DR) is characterised by dysfunction of the retinal neurovascular unit, leading to visual impairment and blindness. Müller cells are key components of the retinal neurovascular unit and diabetes has a detrimental impact on these glial cells, triggering progressive neurovascular pathology of DR. Amongst many factors expressed by Müller cells, interleukin-33 (IL-33) has an established immunomodulatory role, and we investigated the role of endogenous IL-33 in DR. The expression of IL-33 in Müller cells increased during diabetes. Wild-type and Il33−/− mice developed equivalent levels of hyperglycaemia and weight loss following streptozotocin-induced diabetes. Electroretinogram a- and b-wave amplitudes, neuroretina thickness, and the numbers of cone photoreceptors and ganglion cells were significantly reduced in Il33−/− diabetic mice compared with those in wild-type counterparts. The Il33−/− diabetic retina also exhibited microglial activation, sustained gliosis, and upregulation of pro-inflammatory cytokines and neurotrophins. Primary Müller cells from Il33−/− mice expressed significantly lower levels of neurotransmitter-related genes (Glul and Slc1a3) and neurotrophin genes (Cntf, Lif, Igf1 and Ngf) under high-glucose conditions. Our results suggest that deletion of IL-33 promotes inflammation and neurodegeneration in DR, and that this cytokine is critical for regulation of glutamate metabolism, neurotransmitter recycling and neurotrophin secretion by Müller cells.

N-methyl-N-nitrosourea (NMU) is widely used to model oxidative stress and inflammation mediated retinal neurodegeneration. Wedelolactone (WD) is known to have antioxidant, anti-inflammatory, and neuroprotective roles. This study tested the therapeutic potential of WD in NMU-induced retinal neurodegeneration and investigated the underlying mechanisms in mice. NMU (40 mg/kg) was injected intraperitoneally into C57BL/6J mice with/without an intravitreal injection of WD (1 μL/eye, 200 μM). Seven days later, retinal function and structure were evaluated by electroretinography (ERG) and Spectral Domain Optical Coherence Tomography (SD-OCT). The expression of inflammasome components (Aim2, Caspase 1/11, and Il1b/Il18) in the total retina lysate was evaluated by RT-qPCR. In vitro, 661W photoreceptor cells were transfected with synthetic double-strand DNA (Poly(dA:dT)) with/without WD pre-incubation. The aim2-related inflammasome expression was evaluated by RT-qPCR and immunocytochemistry. The production of IL18 was measured by ELISA. NMU treatment significantly impaired A- and B-wave response (ERG) and reduced neuroretina thickness (OCT). This was significantly attenuated upon intravitreal injection of WD. The expression of Aim2, ACasp1, and Casp11 was increased in the retina from NMU-treated mice, and this was prevented by WD treatment. Transfection of Poly(dA:dT) upregulated Aim2, Casp11, and Il18 expression in 661W cells. WD prevented their upregulation and reduced IL18 production. Aim2 inflammasome activation is critically involved in NMU-induced retinal neurodegeneration and WD can protect the retina particularly through the suppression of this inflammasome-linked pathway.

Infection with Plasmodium falciparum carries a significant risk of cerebral malaria (CM). Children are particularly susceptible to human CM (HCM) which manifests as an acute neurovascular encephalopathy leading to high levels of mortality. Occurring in parallel with CM, malarial retinopathy (MR) is readily detected on ophthalmoscopy as one or more of: white-centered retinal hemorrhage, retinal whitening, and vessel discoloration. It leads to several distinct types of blood retinal barrier (BRB) breakdown. The precise molecular mechanisms underpinning CM and MR remain ill-defined, but parasitemia is known to drive progressive neurovascular obstruction and inflammation leading to cerebral and retinal edema and ischemia. Extensive clinical studies in patients with CM have shown that retinal examination is a useful approach for understanding pathology and an indicator for risk of mortality and morbidity. Fully understanding the cellular and molecular mechanisms that underpin CM and MR is important for developing new therapeutic approaches and in this regard the murine model of experimental CM (ECM) has proved to offer considerable value. Much is known about brain pathology in this model although much less is understood about the retina. In this review, we seek to evaluate MR in clinical scenarios and make comparisons with the retina from mice with ECM. Through detailed in vivo and post-mortem studies in the mouse and human retina, this review highlights the links between CM and MR and how this will aid our understanding of the disease progression and pathogenesis.