Cell Death Characteristics Retinal Cell Types Extrinsic apoptosis • Triggered by binding of lethal ligands (FAS/CD95, TNF, TRAIL) to respective death receptor • Caspase-8 activation leading to eventual caspase-9 and caspase-3 activation as the executioner caspase • DNA fragmentation • Endothelial cells • Pericyte • Ganglion cells • Amacrine • S-cones Intrinsic apoptosis • Triggered by intracellular stress (DNA damage, oxidative stress, excitoxicity) • Increased mitochondrial outer membrane permeability • Release of proteins from mitochondria (cytochrome c) • AIF and ENDOG nuclear translocation • DNA fragmentation • Caspase-9 activation leading to caspase-3 activation as the executioner caspase • Endothelial cells • Pericytes • Ganglion cells • Amacrine • S-cones Necrosis • Triggered by excitotoxicity, DNA damage, or binding of lethal ligands (TNF, FasL) • Ubiquitination of RIP1 and subsequent RIP3 activation • Cell death even in the absence of caspase activity • Pericytes Autophagic cell death • Presence of autophagy markers (lipidation of LC3/Atg8) • Increased degradation of autophagic substrates (SQSTM1) • Prevented by inhibition of autophagy • ? Pyroptosis • Triggered by either DAMPs or PAMPs • Assembly of either inflammasome or pyroptosome complex • Caspase-1 activation and subsequent IL-1β or IL-18 • Müller cells Abbreviations: AIF: Apoptosis-inducing Factor; ENDOG: Endonuclease G; TNF: Tumor Necrosis Factor; LC3/Atg8: Microtubule-associated protein 1 light chain 3; SQSTM1: Sequestosome 1; DAMP: Danger Associated Molecular Pattern; PAMP: Pathogen Associated Molecular Pattern

Table 1: Characteristics of modes of cell death and potential retinal cell types undergoing cell death in diabetic retinopathy (for more detailed list of characteristics of cell death modes refer to current NCCD definitions [26]). Retinal cell types were assigned into a cell death category based on identification of at least two characteristics of the respective mode of cell death.