{'fraction_non_alphanumeric': 0.012419006479481642, 'fraction_numerical': 0.004319654427645789, 'mean_word_length': 6.072519083969466, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke

Significance Necroptosis has been defined as a regulated cell death mechanism that can be activated under apoptosis deficient conditions. Here we show that necroptosis can be activated under brain ischemic conditions without inhibition of apoptosis. Furthermore, neuronal necroptosis can be followed by delayed apoptosis after the reduction of TAK1 under ischemic conditions. Our study demonstrates the complex interaction of apoptosis and necroptosis after ischemic brain insult and suggests the therapeutic targeting of RIPK1 kinase for the treatment of stroke. Apoptosis and necroptosis are two regulated cell death mechanisms; however, the interaction between these cell death pathways in vivo is unclear. Here we used cerebral ischemia/reperfusion as a model to investigate the interaction between apoptosis and necroptosis. We show that the activation of RIPK1 sequentially promotes necroptosis followed by apoptosis in a temporally specific manner. Cerebral ischemia/reperfusion insult rapidly activates necroptosis to promote cerebral hemorrhage and neuroinflammation. Ripk3 deficiency reduces cerebral hemorrhage and delays the onset of neural damage mediated by inflammation. Reduced cerebral perfusion resulting from arterial occlusion promotes the degradation of TAK1, a suppressor of RIPK1, and the transition from necroptosis to apoptosis. Conditional knockout of TAK1 in microglial/infiltrated macrophages and neuronal lineages sensitizes to ischemic infarction by promoting apoptosis. Taken together, our results demonstrate the critical role of necroptosis in mediating neurovascular damage and hypoperfusion-induced TAK1 loss, which subsequently promotes apoptosis and cerebral pathology in stroke and neurodegeneration.