The Pathogenesis of Necroptosis-Dependent Signaling Pathway in Cerebral Ischemic Disease

Abstract

Necroptosis is the best-described form of regulated necrosis at present, which is widely recognized as a component of caspase-independent cell death mediated by the concerted action of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Mixed-lineage kinase domain-like (MLKL) was phosphorylated by RIPK3 at the threonine 357 and serine 358 residues and then formed tetramers and translocated onto the plasma membrane, which destabilizes plasma membrane integrity leading to cell swelling and membrane rupture. Necroptosis is downstream of the tumor necrosis factor (TNF) receptor family, and also interaction with NOD-like receptor pyrin 3 (NLRP3) induced inflammasome activation. Multiple inhibitors of RIPK1 and MLKL have been developed to block the cascade of signal pathways for procedural necrosis and represent potential leads for drug development. In this review, we highlight recent progress in the study of roles for necroptosis in cerebral ischemic disease and discuss how these modifications delicately control necroptosis.

Z-ligustilide protects BV-2 microglial cells against oxygen-glucose deprivation/reoxygenation-induced injury by inhibiting NLRP3 inflammasome activation and pyroptosis

“…Recent findings implicated that NLRP3 inflammasome activation was originally participated in the process of brain damage caused by neuroinflammation in ischemic stroke. 24,25 Pringle et al 26 reported that IL-1β strongly potentiated hypoxia-induced neuronal damage. Consistent with these findings, we found that NLRP3 inflammasome was markedly activated as evidenced by the cleavage of caspase-1 and IL-1β in OGD/R microglial cells.…”

Potential application of traditional Chinese medicine in cerebral ischemia—Focusing on ferroptosis

“…During cerebral ischemia, neuronal pyroptosis and necroptosis are extensively affected (Xu et al, 2018;Dong et al, 2018). Pyroptosis is thought to be executed by receptorinteracting protein kinase 3 (RIPK3) and a pseudokinase, mixed lineage kinase domain-like protein (MLKL).…”

The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis

“…The expression of both RIP3 and MLKL demonstrates a significant increase in atherosclerotic plaques compared to normal arteries ( Karunakaran et al, 2016 ). Besides, numerous studies have shown that MLKL-dependent necroptosis is critical in the pathogenesis of brain diseases, especially ischemic brain injury and neurodegenerative diseases ( Zhang et al, 2017 ; Xu et al, 2018a ). Necroptosis has also been implicated in acute kidney injury (AKI) and chronic renal disease ( Imamura et al, 2018 ).…”