c-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway

Yanxia Huang; Shuchao Wang; Fei Huang; Qi Zhang; Bo Qin; Lvshuang Liao; Mi Wang; Hao Wan; Weitao Yan; Dan Chen; Fengxia Liu; Bing Jiang; Dan Ji; Xiaobo Xia; Jufang Huang; Kun Xiong

doi:10.1016/j.aanat.2020.151672

c-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway

Ann Anat. 2021 May:235:151672. doi: 10.1016/j.aanat.2020.151672. Epub 2021 Jan 9.

Authors

Yanxia Huang¹, Shuchao Wang², Fei Huang³, Qi Zhang⁴, Bo Qin⁵, Lvshuang Liao⁴, Mi Wang⁴, Hao Wan⁴, Weitao Yan⁴, Dan Chen⁴, Fengxia Liu⁶, Bing Jiang⁷, Dan Ji⁸, Xiaobo Xia⁸, Jufang Huang⁹, Kun Xiong¹⁰

Affiliations

¹ Department 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.
² Center for Medical Research, The Second Xiangya Hospital of Central South University, Changsha 410013, China.
³ Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
⁴ Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
⁵ Department of Anatomy, Medical College of Hubei Polytechnic University, Huang shi 435003, China.
⁶ Department of Human Anatomy, School of Basic Medical Science, Xinjiang Medical University, Urumqi 830001, China.
⁷ Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha 410008, China.
⁸ Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁹ Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China. Electronic address: huanghufang@csu.edu.cn.
¹⁰ Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China. Electronic address: xiongkun2001@163.com.

PMID: 33434657
DOI: 10.1016/j.aanat.2020.151672

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.

Keywords: GSDMD; ODG/R; Pyroptosis; Retinal neurons; aHIOP; c-FLIP.

MeSH terms

CASP8 and FADD-Like Apoptosis Regulating Protein
Glucose
Oxygen
Phosphate-Binding Proteins
Pyroptosis*
Retinal Neurons*

Substances

CASP8 and FADD-Like Apoptosis Regulating Protein
Phosphate-Binding Proteins
Glucose
Oxygen