Abstract
Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1β, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.
Highlights
Traumatic brain injury (TBI) is one of the most common cause of disability and mortality worldwide both in children and adolescents and may have a strong correlation with neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease [1,2]
This review will provide a brief overview of the pathophysiology of TBI and in particular aims to describe the role played by a complex of proteins known as the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome, in the neuroinflammatory response in TBI, highlighting the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI
Highlights: (1) NLRP3 inflammasome activation stimulates pyroptosis; (2) The activation of the “canonical” pyroptosis recruits caspase-1 resulting from NLRP3 activation; (3) caspase-1 cleaves gasdermin D (GSDMD) which represents the key mediator of pyroptosis; (4) Pyroptosis promotes the release of IL-1β and IL-18, further increasing proinflammatory cytokines levels; (5) The canonical pyroptosis is activated in TBI following NLRP3 recruitment
Summary
Cell membrane disruption due to traumatic brain injury is responsible for the alteration of ions and neurotransmitters equilibrium that modify the membrane potential. Glutamate release is responsible for excitotoxicity, a process that contributes to the pathophysiology of TBI, basically characterized by the increase of glutamate and other neurotransmitters that stimulating NMDA (N-methyl-d-aspartate) and AMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors [14] causing intracellular accumulation of calcium, overproduction of nitric oxide (NO) with consequent formation of free radicals and oxidative stress that disrupting membranes causes DNA damage and promotes pro-death signals [15]. Sci. 2020, 21, 6204 receptors respond to mechanical stress following TBI and GluN2B subunit is considered as a mediator of the mechanosensitive responses, activating pro-death signals This mechanism is strictly linked to the presence of glutamate, the consequent calcium influx is inhibited if glutamate binding sites are occupied by specific blockers [21]. (2) TBI can induce glutamate-independent excitotoxicity, stimulating the release of calcium; (3) The increased levels of ions and glutamate cause DNA damage, oxidative stress activation, proapoptotic signals
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