Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1β (IL-1β), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.
Highlights
Traumatic brain injury (TBI) is a major cause of disability in young adults and contributes to over 30% of injury-related deaths [1]
It demonstrates that the induction of the NLRP3 inflammasome after TBI is coupled with increased interaction with thioredoxininteracting protein (TXNIP), a known activator of NLRP3
It provides the novel insight that NADPH oxidase 2 (NOX2) deletion strongly attenuates NLPR3 inflammasome activation after TBI, an effect that correlated with a reduced interaction of NLRP3 and TXNIP
Summary
Traumatic brain injury (TBI) is a major cause of disability in young adults and contributes to over 30% of injury-related deaths [1]. Neuroinflammation is associated with the progression of neurodegenerative disorders and contributes to the secondary injury after TBI [19,20,21,22] Inflammasomes, such as NOD-like receptors (NLRP) and absent in melanoma 2(AIM 2-) like receptors, are innate immune system sensors of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) that regulate the activation of caspase-1 and promote secretion of proinflammatory cytokines, such as IL-1β and IL-18 [23,24,25]. There is growing evidence that inflammasomes play a role in TBI pathology In support of this contention, high NLRP1, ASC, AIM 2, and caspase-1 expression was detected in the CSF of TBI patients [29,30,31] and correlated with severity of TBI [30]. The results provide evidence that TXNIP may be a key factor mediating the crosstalk between oxidative stress and neuroinflammation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
