c-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway
Yanxia Huang1, Shuchao Wang2, Fei Huang3
1Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China; Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
Abstract:
Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.
Insights
Cellular FLICE-inhibitory protein (c-FLIP) promotes retinal neuronal pyroptosis by cleaving gasdermin D (GSDMD). Reducing c-FLIP expression protects against vision loss and pyroptotic cell death.
Area of Science:
- Ophthalmology
- Cell Biology
- Neuroscience
Background:
- Cellular FLICE-inhibitory protein (c-FLIP) is an anti-apoptotic protein with structural similarities to caspase-8.
- Inflammation and pyroptosis in retinal neurons can be induced by oxygen-glucose deprivation/recovery (OGD/R) and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) models.
- The role of c-FLIP in pyroptotic death of retinal neurons remains largely unknown.
Purpose of the Study:
- To investigate the regulatory role of c-FLIP in pyroptotic death of retinal neurons.
- To determine if c-FLIP regulates pyroptosis through gasdermin D (GSDMD) cleavage.
- To explore c-FLIP as a potential therapeutic target for pyroptosis-related retinal diseases.
Main Methods:
- In vitro induction of retinal neuronal damage using oxygen-glucose deprivation/recovery (OGD/R) and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatments.
- In vivo induction of retinal neuronal damage via acute high intraocular pressure (aHIOP).
- Analysis of pyroptosis-related protein expression and c-FLIP's interaction with GSDMD.
Main Results:
- All three injury models (OGD/R, LPS/ATP, aHIOP) upregulated pyroptosis-related proteins.
- c-FLIP was found to cleave GSDMD, generating the N-terminal (NT) domain, which drives pyroptosis in retinal neurons.
- Knockdown of c-FLIP in vivo reduced visual impairment caused by acute intraocular pressure elevation.
Conclusions:
- c-FLIP promotes retinal neuronal pyroptosis by cleaving GSDMD.
- Decreased c-FLIP expression protects retinal neurons from pyroptotic death by inhibiting GSDMD-NT generation.
- c-FLIP represents a potential therapeutic target for pyroptosis-related ocular diseases.
