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Author Spotlight: Advancing Research in Corneal Opacity Treatment and Regeneration
Published on: August 4, 2023
Suppression of the caspase-1/GSDMD-mediated pyroptotic signaling pathway through dexamethasone alleviates corneal
Yuan Tan1, Min Zhang1, Yingzhe Pan1
1Department of Ophthalmology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China.
Abstract:
The pathological mechanism of corneal injuries mediated by alkali burns are associated with Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 protein (NLRP3)-related corneal sterile inflammation. Whether the executive protein gasdermin D (GSDMD) of pyroptosis mediated by the NLRP3 inflammasome is present in alkali-induced corneal lesions remains unclear. Dexamethasone (Dex) is a commonly used drug for ocular surface diseases that can maintain corneal transparency and anti-inflammatory effects by topical administration. Here, we presented evidence that the effect of Dex on the pyroptosis-related caspase-1/GSDMD pathway in corneal alkali burns (CABs). We assessed the clinical manifestations and histological characteristics of the placebo group, 0.05% Dex group, 0.1% Dex group on day 3 or day 7 postburn and the control group (healthy corneas). The expression of factors (including NLRP3, caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N termini, pro-interleukin(IL)-1β, IL-1β, pro-IL-18 and IL-18) involved in the pyroptosis related caspase-1/GSDMD signaling pathway was demonstrated by molecular experiments in CAB. Alkali burns can upregulate the originally relatively dim expression of NLRP3, caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, pro-IL-1β, pro-IL-18, IL-1β and IL-18 in the healthy corneal epithelium and stroma. However, Dex can reverse the enhanced expression at the two timepoints. Corneal sterile inflammation can activate the NLRP3 inflammasome through the innate immune response mechanism and then activate the pyroptosis-related caspase-1/GSDMD signaling pathway. In addition, Dex can inhibit pyroptosis through this pathway.
Insights
Alkali burns cause corneal sterile inflammation via the NLRP3 inflammasome and pyroptosis pathway. Dexamethasone (Dex) effectively inhibits this pathway, reducing corneal damage.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Corneal alkali burns induce sterile inflammation linked to NLRP3 inflammasome activation.
- The role of gasdermin D (GSDMD) in pyroptosis during alkali-induced corneal lesions is not fully understood.
Purpose of the Study:
- To investigate the effect of Dexamethasone (Dex) on the caspase-1/GSDMD pyroptosis pathway in corneal alkali burns (CABs).
- To elucidate the mechanism of Dex in mitigating corneal inflammation and damage.
Main Methods:
- Assessment of clinical and histological features in control, placebo, and Dex-treated groups (0.05% and 0.1%) at 3 and 7 days post-burn.
- Molecular analysis of key pyroptosis pathway components (NLRP3, caspase-1, GSDMD, IL-1β, IL-18) in corneal tissues.
Main Results:
- Alkali burns significantly upregulated NLRP3, caspase-1, GSDMD, and related cytokines (IL-1β, IL-18) in corneal tissues.
- Dex treatment effectively reversed the enhanced expression of these pyroptosis markers.
- Dex demonstrated anti-inflammatory and corneal transparency-preserving effects.
Conclusions:
- Corneal sterile inflammation following alkali burns activates the NLRP3 inflammasome and the caspase-1/GSDMD pyroptosis pathway.
- Dexamethasone inhibits pyroptosis via this pathway, offering a therapeutic strategy for corneal alkali burns.
