Treatment with interleukin‐33 is non‐toxic and protects retinal pigment epithelium in an ageing model of outer retinal degeneration

Clare, Alison J; Copland, David A; Nicholson, Lindsay B.; Liu, Jian; Neal, Chris; Moss, Stephen E.; Dick, Andrew D.; Theodoropoulou, Sofia

doi:10.1111/jcmm.16000

Cited by 5 publications

(3 citation statements)

References 16 publications

(25 reference statements)

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“…IL‐33 might also be offered as a valuable therapeutic for restoring tissue homeostasis in dry AMD patients. The delivery of exogenous recombinant IL‐33 protein using intravitreal injections also demonstrated protection against RPE degeneration and maintained metabolic retinal homeostasis in CFH +/− aged mice fed on a high fat diet (Clare et al, 2020), suggesting further evidence for IL‐33 preventing AMD progression and an exciting avenue.…”

Section: Emerging Therapies and Their Delivery For Treating Amdmentioning

confidence: 99%

Emerging therapies and their delivery for treating age‐related macular degeneration

Thomas

Sim

Lee

et al. 2021

British J Pharmacology

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Age-related macular degeneration (AMD) is the most common cause of blindness in the Western world and is characterised in its latter stages by retinal cell death and neovascularisation and earlier stages with the loss of parainflammatory homeostasis.Patients with neovascular AMD (nAMD) are treated with frequent intraocular injections of anti-vascular endothelial growth factor (VEGF) therapies, which are not only unpopular with patients but carry risks of sight-threatening complications. A minority of patients are unresponsive with no alternative treatment available, and some patients who respond initially eventually develop a tolerance to treatment. New therapeutics with improved delivery methods and sustainability of clinical effects are required, in particular for non-neovascular AMD (90% of cases and no current approved treatments). There are age-related and disease-related changes that occur which can affect ocular drug delivery. Here, we review the latest emerging therapies for AMD, their delivery routes and implications for translating to clinical practice.

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Section: Emerging Therapies and Their Delivery For Treating Amdmentioning

confidence: 99%

Emerging therapies and their delivery for treating age‐related macular degeneration

Thomas

Sim

Lee

et al. 2021

British J Pharmacology

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“…Importantly, treatment of RPE cells with recombinant IL-33 protects against H 2 O 2 induced oxidative stress [ 80 ], suggesting IL-33/ST2 signalling could have therapeutic potential for RPE in AMD. Accordingly, we have shown IL-33 delivery in the aged Cfh +/− high-fat diet-fed model of outer retinal degeneration can protect against RPE loss and maintain expression of key metabolic proteins in the retina [ 88 ]. Additional evidence shows that stimulation of AMPK by metformin protects against photoreceptor and RPE damage in retinal degeneration models, including light-induced damage [ 89 ], and that activation of AMPK converges on pathways promoting autophagy [ 90 ].…”

Section: Therapeutic Development and The Potential Of Il-33 For Treat...mentioning

confidence: 99%

Unravelling the therapeutic potential of IL-33 for atrophic AMD

Clare

Jian

Copland

et al. 2021

Eye

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Age-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases “wet” or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD.

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“…Furthermore, it has been shown that endogenous IL-33 exerts control over mitochondrial respiration in the retinal pigment epithelium (RPE) by facilitating oxidative pyruvate catabolism to maintain homeostasis, which thus confirms the role of IL-33 as a key metabolic checkpoint regulator in the RPE, exerting profound effects on retinal metabolism ( Scott et al, 2021 ). In addition, the protective capability of exogenous IL-33 against RPE loss and for retinal metabolic homeostasis has been shown in a dysregulated immune-mediated insidious model of outer retinal degeneration ( Clare et al, 2020 ). IL-33 also limits pathology by suppressing the activation and migration of choroidal endothelial cells and fibroblasts in the context of choroidal neovascularisation ( Theodoropoulou et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

IL-33 regulates Müller cell-mediated retinal inflammation and neurodegeneration in diabetic retinopathy

Augustine,

Pavlou,

Harkin

et al. 2023

Disease Models &Amp; Mechanisms

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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.

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Treatment with interleukin‐33 is non‐toxic and protects retinal pigment epithelium in an ageing model of outer retinal degeneration

Cited by 5 publications

References 16 publications

Emerging therapies and their delivery for treating age‐related macular degeneration

Emerging therapies and their delivery for treating age‐related macular degeneration

Unravelling the therapeutic potential of IL-33 for atrophic AMD

IL-33 regulates Müller cell-mediated retinal inflammation and neurodegeneration in diabetic retinopathy

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