Pyroptosis: A New Insight Into Eye Disease Therapy

Abstract

Pyroptosis is a lytic form of programmed cell death mediated by gasdermins (GSDMs) with pore-forming activity in response to certain exogenous and endogenous stimuli. The inflammasomes are intracellular multiprotein complexes consisting of pattern recognition receptors, an adaptor protein ASC (apoptosis speck-like protein), and caspase-1 and cause autocatalytic activation of caspase-1, which cleaves gasdermin D (GSDMD), inducing pyroptosis accompanied by cytokine release. In recent years, the pathogenic roles of inflammasomes and pyroptosis in multiple eye diseases, including keratitis, dry eyes, cataracts, glaucoma, uveitis, age-related macular degeneration, and diabetic retinopathy, have been continuously confirmed. Inhibiting inflammasome activation and abnormal pyroptosis in eyes generally attenuates inflammation and benefits prognosis. Therefore, insight into the pathogenesis underlying pyroptosis and inflammasome development in various types of eye diseases may provide new therapeutic strategies for ocular disorders. Inhibitors of pyroptosis, such as NLRP3, caspase-1, and GSDMD inhibitors, have been proven to be effective in many eye diseases. The purpose of this article is to illuminate the mechanism underlying inflammasome activation and pyroptosis and emphasize its crucial role in various ocular disorders. In addition, we review the application of pyroptosis modulators in eye diseases.

Suppression of NLRP3/Caspase-1/GSDMD Mediated Corneal Epithelium Pyroptosis Using Melatonin-Loaded Liposomes to Inhibit Benzalkonium Chloride-Induced Dry Eye Disease

“…That may be a deep underlying mechanism for the promoted transduction of NLRP3/Caspase-1/GSDMD signaling axis, which consequent a pyroptotic death of corneal epithelium in BAC-DED. Though several reports have indicated the role of pyroptosis in the development of DED, 14 , 63 , 64 the BAC-induced corneal epithelium pyroptosis has not been reported before. The present study provided new insights into the adverse effects of BAC, which can serve as a new target for the protection of corneal epithelium when applying BAC as a preservative in eye drops.…”

Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response

“…Furthermore, emerging studies have shown that in lens/LECs, aging and oxidative stress can induce various types of program cell death, such as apoptosis, pyroptosis, and ferroptosis [6,51,131,132]. It has been established that these program cell deaths are linked to the onset of cataractogenesis [133][134][135][136]. It is worth mentioning that in vitro experiments conducted with Hyd at concentrations of 20 to 50 µM appear to be pharmacologically and physiologically relevant.…”

Astragaloside IV alleviates oxidative stress‑related damage via inhibiting NLRP3 inflammasome in a MAPK signaling dependent pathway in human lens epithelial cells

“…The thioredoxin‐interacting protein can be dissociated by excessive ROS and binds to the inflammasome assembly followed by the activation of NLRP3 inflammasome (Tang et al, 2019). The upregulation of NLRP3 transcription promotes recruitment of the adapter ASC and, in turn, recruiting procaspase 1, which plays a crucial role in pyroptosis and multiple eye diseases (Shao et al, 2016; Y. Zhang et al, 2021). ASC serves as one of the platforms for the proteolytic maturation of caspase‐1, and caspase 1 induces ASC‐mediated necrosis (Motani et al, 2011).…”