Necroptosis: A Novel Pathway in Neuroinflammation

Abstract

Neuroinflammation is a complex inflammatory process in the nervous system that is expected to play a significant role in neurological diseases. Necroptosis is a kind of necrosis that triggers innate immune responses by rupturing dead cells and releasing intracellular components; it can be caused by Toll-like receptor (TLR)-3 and TLR-4 agonists, tumor necrosis factor (TNF), certain microbial infections, and T cell receptors. Necroptosis signaling is modulated by receptor-interacting protein kinase (RIPK) 1 when the activity of caspase-8 becomes compromised. Activated death receptors (DRs) cause the activation of RIPK1 and the RIPK1 kinase activity-dependent formation of an RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL), which is complex II. RIPK3 phosphorylates MLKL, ultimately leading to necrosis through plasma membrane disruption and cell lysis. Current studies suggest that necroptosis is associated with the pathogenesis of neuroinflammatory diseases, such as Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. Inhibitors of necroptosis, such as necrostatin-1 (Nec-1) and stable variant of Nec (Nec-1s), have been proven to be effective in many neurological diseases. The purpose of this article is to illuminate the mechanism underlying necroptosis and the important role that necroptosis plays in neuroinflammatory diseases. Overall, this article shows a potential therapeutic strategy in which targeting necroptotic factors may improve the pathological changes and clinical symptoms of neuroinflammatory disorders.

Inhibition of RIP3 increased ADSC viability under OGD and modified the competency of adipogenesis, angiogenesis, and inflammation regulation

“…In tumor necrosis factor receptor 1 (TNFR1) signaling, TNFα binds with TNFR1, inducing phosphorylation of RIP1 and downstream activities. When caspase 8 was inhibited, phosphorylated RIP1 recruited phosphorylated RIP3 to form necrotic bodies, and RIP3 induced the phosphorylation of MLKL, which oligomerized and migrated to the membrane, resulting in cell membrane disintegration, cell necrosis, and release of a large number of damage-related molecular patterns (DAMPs) [ 32 ]. Through the blot results of ADSCs after OGD treatment for 4 h, the necroptosis classical pathway proteins RIP3, pRIP3, and pMLKL were significantly higher than those in the control group, suggesting that necroptosis may be closely related to the changes in ADSCs in the OGD environment.…”

Inhibition of Neuronal Necroptosis Mediated by RIPK1 Provides Neuroprotective Effects on Hypoxia and Ischemia In Vitro and In Vivo

“…These data allow us to take a new look at the molecular pathogenetic pathways of hypoxic ischemic damage to nerve cells and consider RIP1 kinase as a potential therapeutic target for neuroprotection. There is also evidence of the important role of necroptosis in neurodegenerative processes in Alzheimer’s and Parkinson’s diseases, as well as in the development of secondary injuries in traumatic brain injury [ 7 , 21 ].…”

“…Activated death receptors (DR) cause RIPK1 phosphorylation, which leads to the formation of the RIPK1-RIPK3 complex called complex IIb. The formation of this complex leads to phosphorylation of the mixed lineage kinase domain-like protein (MLKL), which ultimately leads to MLKL-mediated necroptosis resulting in plasma membrane destruction and cell lysis [ 7 ]. In the case of a mitochondria dysfunction, the production of reactive oxygen species increases significantly.…”

Radiosynthesis and Evaluation of Cyclohexyl (5-(2-[11C-Carbonyl]acetamidobenzo[d]thiazol-6-yl)-2-Methylpyridin-3-yl)Carbamate ([11C]PK68) As a New Radioligand For Imaging Receptor-Interacting Protein 1 Kinase

“…Receptor-interacting protein 1 kinase (RIPK1) is a key regulator of neuronal death and is involved in apoptosis and necroptosis; it is related to several disorders including neuroin ammation, neurodegeneration, and carcinogenesis (Chan et al 2019;DeRoo et al 2020;Yu et al 2021;Yuan et al 2019). RIPK1 is a member of the RIP kinase family and contains a Ser/Thr kinase domain N-terminal, an intermediate domain, and a death domain C-terminal (Sunde et al 1997;Zhang et al 2018a).…”