Role of necroptosis in traumatic brain and spinal cord injuries

Abstract

Background: Traumatic brain injury (TBI) and spinal cord injury (SCI) are capable of causing severe sensory, motor and autonomic nervous system dysfunctions. However, effective treatments for TBI and SCI are still unavailable, mainly because the death of nerve cells is uncontrollable. Necroptosis is a type of programmed cell death and a critical mechanism in the process of neuronal cell death. However, the role of necroptosis has not been comprehensively defined in TBI and SCI.

Aim of review: This review aimed to summarize the role of necroptosis in central nervous system (CNS) trauma and its therapeutic implications and present important suggestions for researchers conducting in-depth research.

Key scientific concepts of review: Necroptosis is orchestrated by a complex comprising the receptor-interacting protein kinase (RIPK)1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) proteins. Mechanistically, RIPK1 and RIPK3 form a necrosome with MLKL. After MLKL dissociates from the necrosome, it translocates to the plasma membrane to induce pore formation in the membrane and then induces necroptosis. In this review, the necroptosis signalling pathway and the execution of necroptosis are briefly discussed. In addition, we focus on the existing information on the mechanism by which necroptosis participates in CNS trauma, particularly in the temporal pattern of RIPKs and in different cell types. Furthermore, we describe the association of miRNAs and necroptosis and the relationship between different types of CNS trauma cell death. Finally, this study highlights agents likely capable of curtailing such a type of cell death according to results optimization and CNS trauma and presents important suggestions for researchers conducting in-depth research.

Keywords: CNS trauma; Cell death; Necroptosis; Spinal cord injury; Traumatic brain injury.

Graphical abstract

Fig. 1

Caspase crosstalk pathways in necroptosis. The assembly of complex I, composed of TRADD, RIPK1, TRAF2/5, cIAP1/2 and LUBAC, is triggered by TNFR1 ligation. cIAP recruits the LUBAC complex, causing the M1 ubiquitination of RIPK1. The binding of NEMO is a significant modulator of NF-kB, and the polyubiquitin chain of RIPK1 acts as a scaffold. NEMO functions as a regulatory subunit inside the IkB kinase (IKK) complex, which is needed to activate IKK. Activated IKK subsequently inactivates IKB, thus activating NF-kB and its transcription of pro-survival and pro-inflammatory genes. Deubiquitination of RIPK1 by CYLD and A20 can result in RIPK1 dissociating from complex I; then, the complex recruits TRADD, FADD and pro-caspase-8 and forms complex IIa, which activates apoptosis. When the expression of cIAP, TAK1 or NEMO is inhibited, complex I transformes into complex IIb to induce necroptosis, which consists of RIPK1, RIPK3, Fas-associated death domain (FADD), and caspase-8. The change in cells from survival to death is suggested by the conversion from complex I to complex II. Complex IIa is composed of TRADD, FADD, RIPK1 and caspase-8. Caspase-8 cleaves downstream caspases as caspase-3/7 are activated inside complex IIa, thus leading to apoptosis, while RIPK1 and RIPK3 are cleaved and inactivated to terminate necrosis. For complex IIb, in the case of caspase-8 inhibition, the RIPK homotypic interaction motif (RHIM) of RIPK3 allows it to bind to RIPK1 before phosphorylation. Consequently, MLKL is recruited and phosphorylated to generate necrosomes. Then, phosphorylated MLKL moves from the cytosol to the plasma and intracellular membranes. Membrane pores develop due to MLKL oligomerization, which leads to membrane fracture. Ultimately, necroptosis occurs.

Fig. 2

Targeting necroptosis-regulated cell death for potenticaly therapeutic implications in CNS trauma. Under the stimulation of CNS trauma, complex I forms first and leads to the formation of complex IIb. Then, complex IIb recruits and phosphorylates MLKL to form necrosomes composed of RIPK1, RIPK3, and MLKL. According to the components of necrosomes, drugs targeting various targets have been developed to inhibit necroptosis. Nec-1 combines with RIPK1 and MLKL to inhibit necroptosis. In addition, GSK2982772, as a novel inhibitor of RIPK1, also has a good effect on inhibiting necroptosis. GSK'872, GSK'843 and GSK'840 are the preferable inhibitors for targeting RIPK3. Dabrafenib, another RIPK3 inhibitor, has been approved for clinical use, while the new RIPK3 inhibitor HS-1371 has great potential. There are few reports about small-molecule inhibitors targeting MLKL; Nec-1 and NSA may be the only drugs to target MLKL.