Role of pyroptosis in spinal cord injury and its therapeutic implications

Abstract

Background: Currently, spinal cord injury (SCI) is a pathological incident that triggers several neuropathological conditions, leading to the initiation of neuronal damage with several pro-inflammatory mediators' release. However, pyroptosis is recognized as a new programmed cell death mechanism regulated by the stimulation of caspase-1 and/or caspase-11/-4/-5 signaling pathways with a series of inflammatory responses.

Aim: Our current review concisely summarizes the potential role of pyroptosis-regulated programmed cell death in SCI, according to several molecular and pathophysiological mechanisms. This review also highlights the targeting of pyroptosis signaling pathways and inflammasome components and its therapeutic implications for the treatment of SCI.

Key scientific concepts: Multiple pieces of evidence have illustrated that pyroptosis plays significant roles in cell swelling, plasma membrane lysis, chromatin fragmentation and intracellular pro-inflammatory factors including IL-18 and IL-1β release. In addition, pyroptosis is directly mediated by the recently discovered family of pore-forming protein known as GSDMD. Current investigations have documented that pyroptosis-regulated cell death plays a critical role in the pathogenesis of multiple neurological disorders as well as SCI. Our narrative article suggests that inhibiting the pyroptosis-regulated cell death and inflammasome components could be a promising therapeutic approach for the treatment of SCI in the near future.

Keywords: AIM2, Absent in melanoma 2; ASC, apoptosis-associated speck-like protein; ATP, Adenosine triphosphate; BBG, Brilliant blue G; CCK-8, Cell Counting Kit-8; CNS, central nervous system; CO, Carbon monoxide; CORM-3, Carbon monoxide releasing molecle-3; Caspase-1; Cx43, Connexin 43; DAMPs, Damage-associated molecular patterns; DRD1, Dopamine Receptor D1; ECH, Echinacoside; GSDMD, Gasdermin D; Gal-3, Galectin-3; H2O2, Hydrogen peroxide; HO-1, Heme oxygenase-1; IL-18, Interleukin-18; IL-1β, Interleukin-1 beta; IRE1, Inositol requiring enzyme 1; JOA, Japanese orthopedics association; LPS, Lipopolysaccharide; NDI, Neck data index; NF-κB, Nuclear factor-kappa B; NLRP1, NOD-like receptor protein 1; NLRP1b, NOD-like receptor protein 1b; NLRP3; NLRP3, Nucleotide-binding domain-like receptor protein 3; Neuroinflammation; Nrf2, Nuclear factor erythroid 2-related factor 2; OPCs, Oligodendrocyte progenitor cells; PAMPs, Pathogen-associated molecular patterns; PRRs, Pattern recognition receptors; Pyroptosis; ROS, Reactive oxygen species; Spinal cord injury; TLR4, Toll-like receptor 4; TXNIP, Thioredoxin-interacting protein; Therapeutic implications; double stranded DNAIR, Ischemia reperfusion; si-RNA, Small interfering RNA.