Longitudinal and simultaneous profiling of 11 modes of cell death in mouse retina post-optic nerve injury. (September 2022)

• Record Type: Journal Article
• Authors: Yao, Yao; Xu, Yanxuan; Liang, Jia-Jian; Zhuang, Xi; Ng, Tsz Kin
• Is Part Of: Experimental eye research. Volume 222(2022)
• Publication Date: 2022-09
• Subjects: Modes of cell death -- Retinal ganglion cells -- Optic nerve injury -- Retina -- Longitudinal profiling; 4-HNE 4-hydroxynonenal -- Actb beta-actin -- ANOVA analysis of variance -- Atg7 autophagy related 7 -- Becn1 beclin 1 -- Cdkn2a cyclin dependent kinase inhibitor 2A -- Dlat dihydrolipoamide S-acetyltransferase -- Fdx1 ferredoxin 1 -- GCL ganglion cell layer -- Gpx4 glutathione peroxidase 4 -- INL inner nuclear layer -- IPL inner plexiform layer -- Mertk MER proto-oncogene, tyrosine kinase -- Mfge8 milk fat globule EGF and factor V/VIII domain containing -- NGS normal goat serum -- ON optic nerve -- ONL outer nuclear layer -- OPL outer plexiform layer -- Parp1 poly(ADP-ribose) polymerase 1 -- Ppif peptidylprolyl isomerase F -- RIPA radio-immunoprecipitation assay -- Ripk1 receptor interacting serine/threonine kinase 1 -- Ripk3 receptor interacting serine/threonine kinase 3 -- RGC retinal ganglion cell -- Sarm1 sterile alpha and HEAT/Armadillo motif containing 1; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2022.109159
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Retinal ganglion cell (RGC) death is a critical pathological trigger leading to irreversible visual impairment and blindness after optic nerve (ON) injury. Yet, there is still no effective clinical treatment to rescue RGC death after ON injury. Understanding the involvement of different modes of cell death post-ON injury could facilitate the development of targeting treatments against RGC death. Herein we aimed to characterize the regulation of 11 modes of cell death simultaneously and longitudinally in mouse retina post-ON injury. The number of RGCs gradually decreased from Day 3–14 in mice post-ON injury. Increase in the apoptosis (cleaved caspase-3), autolysis (cleaved cathespin B) and pyroptosis (cleaved caspase-1) marker expression in the retina began at Day 3 post-ON injury. Meanwhile, the markers for autophagy ( Atg7 and Becn1 ) and phagocytosis ( Mfge8 and Mertk ) were downregulated from Day 1 to Day 5. Additionally, the expression of ferroptosis marker (4-hydroxynonenal) was upregulated from Day 7 to Day 14 post-ON injury following the early reduction of Gpx4 . Yet, the reduction of parthanatos, sarmoptosis, and mitochondrial permeable transition could be related to autophagy and apoptosis. The markers for necroptosis did not show significant changes post-ON injury. In summary, this study revealed that the activation of apoptosis, autolysis, pyroptosis and ferroptosis, together with the early downregulation of autophagy and phagocytosis, are the major modes of cell death involved in the RGC death post-ON injury. Simultaneously targeting multiple modes of cell death at different time courses could be a potential treatment approach against RGC death for traumatic optic neuropathy. Highlights: RGCs reduce rapidly from Day 3 to Day 10 and steadily from Day 10 to Day 14 post-ON injury. Apoptosis, autolysis, and pyroptosis activate at early phase post-ON injury with downregulated autophagy and phagocytosis. Ferroptosis is gradually activated in mouse retina along the time course post-ON injury.