Connexin43 hemichannel block inhibits NLRP3 inflammasome activation in a human retinal explant model of diabetic retinopathy
| Autor: | Odunayo O Mugisho, Ilva D. Rupenthal, Colin R. Green, Avik Shome, Henry H. Louie, Charisse Y J Kuo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Inflammasomes medicine.medical_treatment Inflammation Proinflammatory cytokine 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine In vivo NLR Family Pyrin Domain-Containing 3 Protein medicine Humans Benzopyrans Aged Aged 80 and over Innate immune system Diabetic Retinopathy Microscopy Confocal business.industry Inflammasome Middle Aged Sensory Systems Ophthalmology 030104 developmental biology Cytokine Connexin 43 Benzamides 030221 ophthalmology & optometry Cancer research Female medicine.symptom business Cell activation NLRP3 inflammasome complex medicine.drug |
| Zdroj: | Experimental eye research. 202 |
| ISSN: | 1096-0007 |
| Popis: | Diabetic retinopathy (DR), the most common ocular complication associated with diabetes, is a chronic vascular and inflammatory disease that leads to vision loss. The inflammasome pathway, a key part of the innate immune system, is required to activate chronic inflammation in DR. Unfortunately, current therapies for DR target pathological signs that are downstream of the inflammasome pathway, making them only partly effective in treating the disease. Using in vitro and in vivo DR models, it was discovered that connexin43 hemichannel blockers can inhibit activation of the inflammasome pathway. However, those studies were conducted using in vitro cell culture and in vivo animal disease models that are predictive but do not, of course, like any model, completely replicate the human condition. Here, we have developed an addition to our armamentarium of useful models, an ex vivo human organotypic retinal culture model of DR by exposing human donor retinal explants to a combination of high glucose (HG) and pro-inflammatory cytokines, interleukin-1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α). We hypothesized that in this model, connexin43 hemichannel block would protect against NLRP3 inflammasome complex assembly which would in turn decrease signs of inflammation characteristic of DR. To test our hypothesis, molecular changes in the inflammatory and inflammasome pathway were assessed using immunohistochemistry and a Luminex cytokine release assay. Our results showed that the human retinal explant DR model was associated with increased inflammation and activation of the inflammasome pathway, characteristic of the human condition. Furthermore, we showed that by blocking connexin43 hemichannels with the hemichannel modulator, tonabersat, we were able to prevent NLRP3 inflammasome complex assembly, Muller cell activation, as well as release of pro-inflammatory cytokines and VEGF. This further supports the possible use of connexin43 hemichannel blockers as potential new therapies for DR. |
| Databáze: | OpenAIRE |
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