The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

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.

Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of pyroptosis and neuroinflammation

“…Pyroptosis was defined as an inflammatory‐mediated and caspase‐1‐dependent type of programmed cell death, which was only recently discovered (Bergsbaken et al, 2009; Magupalli et al, 2020). Inflammasome activation and pyroptosis have been confirmed in traumatic brain injury, acute hemorrhagic stroke, and experimental SAH, etc (Che et al, 2020; Chen, Li, et al, 2020; Irrera et al, 2020; Xu et al, 2020), and plays a vital role in EBI. In many recent studies, inflammasome and pyroptosis had been demonstrated to be a vital mechanism in EBI after SAH (Xu et al, 2020; Yuan et al, 2020).…”

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury

“…This family of pattern recognition receptors includes three elements, namely a sensor molecule, an adaptor protein, and an effector component. Several inflammasomes have been identified in mammals, with the NLRP3 and NLRP1 being the most extensively studied in TBI [ 115 , 116 ]. Within the CNS, NLRP3 is mainly located in microglia, but it has also been identified in oligodendrocytes and astrocytes, while NLRP1 and a third sensor, AIM2, are expressed in neurons [ 116 , 117 , 118 ].…”

“…The activating stimulus induces the assembly of the complete inflammasome, which is made up of seven NLRPs inflammasomes molecules arranged in a ring structure. The multimeric complex allows for the cleavage of pro-caspase-1 into the active isomer, caspase-1, which then cleaves pro-IL-1β and pro-IL-18 into active IL-1β and IL-18, respectively [ 116 , 117 , 118 ]. These cytokines are involved in the innate immune response to infections and tissue damage by creating a pro-inflammatory environment and are related to several inflammatory diseases [ 118 , 119 ].…”

Bibliometric Analysis of the Inflammasome and Pyroptosis in Brain

“…Pyroptosis is related to multiple diseases and can be involved in a variety of acute and chronic injuries ( Alfonso-Loeches et al, 2014 ; Israelov et al, 2020 ; Xu et al, 2019 ; Zeng et al, 2019 ). In recent years, studies have found that inflammation is widely found in the various central nervous system (CNS) diseases ( Figure 1 ), and the occurrence and development of traumatic brain injuries (TBI) ( de Rivero Vaccari et al, 2009 ; Liu et al, 2018 ; Chen et al, 2019c ; Irrera et al, 2020 ), stroke ( Abulafia et al, 2009 ; Poh et al, 2019 ), Alzheimer’s disease (AD) ( Halle et al, 2008 ; Flores et al, 2018 ), Parkinson’s disease (PD) ( Codolo et al, 2013 ; Yan et al, 2020 ), multiple sclerosis (MS) ( Soulika et al, 2009 ; McKenzie et al, 2018 ), Huntington’s disease (HD) ( Glinsky, 2008 ; Paldino et al, 2020 ), spinal cord injury (SCI) ( de Rivero Vaccari et al, 2008 ; de Rivero Vaccari et al, 2012 ; Jiao et al, 2020 ), and other diseases depend on the inflammasome. Pyroptosis contributes to the pathogenesis of sepsis-associated encephalopathy (SAE), with inhibition of either caspase-1 or NLRP3 improving survival and reducing SAE-associated neurocognitive deficits, neuroinflammation, and GSDMD-mediated pyroptosis in mouse models ( Fu et al, 2019 ; Xu et al, 2019 ).…”

“…Clinical evidence suggests that patients with TBI are higher cerebrospinal fluid (CSF) levels of the inflammasome proteins NLRP3, AIM2, ASC, and caspase-1 (Adamczak et al, 2012;Adamczak et al, 2014;Wallisch et al, 2017), and CSF NLRP3 levels are increased after TBI in infants and children and independently associated with younger age and poor outcome (Wallisch et al, 2017). Furthermore, NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes have been confirmed to be involved in TBI pathology in animal models, highlighting the multiformity of danger signals resulting from tissue injury (Adamczak et al, 2014;Freeman and Ting, 2016;Irrera et al, 2020). NLRP3 knockout or pharmacological inhibitor is beneficial for the outcomes of TBI animal models through inhibiting pyroptosis and neuroinflammation (Chen et al, 2019c;Chen et al, 2019d;Liu et al, 2018;O'Brien et al, 2020;Swanson et al, 2019), so NLRP3 may be a potentially effective biomarker and therapeutic target for TBI (O'Brien et al, 2020;Swanson et al, 2019).…”