Inhibiting the NLRP3 inflammasome pathway: An effective way to treat chronic inflammation in experimental autoimmune uveitis.

Abstract

This study aimed to determine whether topical and/or oral administration of a nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome blocker can reduce signs of chronic inflammation in experimental autoimmune uveitis (EAU) mice. Mice were treated daily with the inflammasome blocker, tonabersat, orally, topically or in combination in comparison to topical dexamethasone over a period of 12 weeks. Ocular assessments using fundus and optical coherence tomography (OCT) images were carried out weekly. At the end of the study, ocular tissues were collected, and immunohistochemistry was performed to assess general retinal inflammation (cluster of differentiation (CD)45, CD68 and interleukin (IL)-17A), inflammasome activation (NLRP3 and cleaved caspase-1 (CC1)), and microglial activation and infiltration (glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule-1 (Iba-1)). Results showed that all treatments reduced the severity of ocular inflammation in fundus and OCT images with the tonabersat combination therapy being superior compared to oral or topical tonabersat alone, and as effective as topical dexamethasone. Interestingly, immunohistochemical analysis suggested that while dexamethasone reduced general inflammatory markers, it had minimal effect on the inflammasome pathway. All tonabersat treatment regimens, on the other hand, were effective in not only reducing general inflammation but also significantly inhibiting the inflammasome pathway. This study supports the idea that blocking the inflammasome pathway is a potential way to resolve the underlying cause of chronic inflammation potentially reducing disease relapse often seen with non-infectious uveitis.