Potential immunotherapies for traumatic brain and spinal cord injury

Abstract

Traumatic injury of the central nervous system (CNS) including brain and spinal cord remains a leading cause of morbidity and disability in the world. Delineating the mechanisms underlying the secondary and persistent injury versus the primary and transient injury has been drawing extensive attention for study during the past few decades. The sterile neuroinflammation during the secondary phase of injury has been frequently identified substrate underlying CNS injury, but as of now, no conclusive studies have determined whether this is a beneficial or detrimental role in the context of repair. Recent pioneering studies have demonstrated the key roles for the innate and adaptive immune responses in regulating sterile neuroinflammation and CNS repair. Some promising immunotherapeutic strategies have been recently developed for the treatment of CNS injury. This review updates the recent progress on elucidating the roles of the innate and adaptive immune responses in the context of CNS injury, the development and characterization of potential immunotherapeutics, as well as outstanding questions in this field.

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

“…Spinal cord injury (SCI) is a serious condition that affects bodily function. It has been reported to affect over 2.5 million people worldwide with an annual incidence of 40-60 per million populaces (Kumar et al, 2018;Putatunda et al, 2018). In SCI, after the initial mechanical damages, other pathophysiologic mechanisms occur in the spinal cord, including inflammation, oxidative stress, edema, and mitochondrial dysfunction (Quadri et al, 2018), which work toward post-SCI tissue and functional reconstruction (Hausmann, 2003).…”

CD73 alleviates GSDMD-mediated pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

“…Secondary injury is persistent and diffuse, and is characterized by delayed glial and neuronal death, which expands the damaged site and can lead to progressive neurodegeneration [27] , [28]. Neuroinflammation initiated by the innate immune response is a key pathological factor in the secondary injury after CNS trauma, and is therefore a promising therapeutic target [2] [6]. An essential step in secondary CNS damage is pyroptosis due to activation of the cytoplasmic inflammasome complex [7].…”

“…Around 240,000-337,000 people are afflicted with SCI in the United States alone, and this number is estimated to grow by 17,000 annually [1]. Nearly 52% of these patients are paraplegic and 47% are quadriplegic [2]. The pathogenesis of SCI is complex and can be divided into two phases [3] -a transient initial traumatic phase, and a long-lasting secondary phase characterized by secretion of cytokines and chemokines at the lesion site and neurological damage [4].…”

CD73 Alleviates GSDMD-Mediated Pyroptosis in Spinal Cord Injury Through PI3K/AKT/Foxo1 Signaling

“…Part of the secondary injury is characterized by persistence and diffuseness, including delayed glial and neuron cells death, leading to significant expansion of the damage site to higher segments and progressive neurodegeneration [29] , [30]. Neuroinflammation initiated by the innate immune response plays an important role in the pathology of secondary injury after CNS trauma, and inhibition of inflammation becomes a potential therapy for such injury [2] [6]. More recently, the scientific community has determined that the activation of cytoplasmic inflammasome complex leading to pyroptosis was an essential step of neuroinflammation in secondary CNS damage [7].…”

“…About 240,000-337,000 people live with SCI in United States, and this figure is thought to grow by 17,000 annually [1]. Nearly 52% of these patients are paraplegic and 47% are considered quadriplegic [2]. Presently, no effective 3 pharmacological therapy exists.…”