NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

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.

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…In addition, a number of recent studies have found that pharmacological treatments that directly or indirectly target this inflammasome can reduce its activity following moderate-to-severe TBI. These treatments are broadly broken into four groups: (i) treatments derived from naturally occurring compounds (e.g., mangiferin [83], omega-3 fatty acids [71], and apocynin [84]); (ii) repurposed medications (e.g., propofol [85], and telmisartan [86]); (iii) inhibitors of NLRP3-associated molecules (e.g., ASC antibodies [87], NF-κB inhibitor, Bay 11-7082 [88][89][90][91]); and (iv) specific NLRP3 inflammasome inhibitors (e.g., MCC950 [69], JC-124 [92]). While the first three treatment categories have been shown to decrease NLRP3 inflammasome activity as well as demonstrating a neuroprotective effect, they do not target NLRP3 activation specifically.…”

“…Given the increasing awareness that neuroinflammation can interact with other aspects of TBI pathophysiology, it is likely that alterations or manipulation of the NLRP3 inflammasome will have multiple pathophysiological consequences. For example, recent studies have found that a relationship exists between neuroinflammation, oxidative stress, and blood-brain barrier permeability after TBI [84,108,109]. The involvement of the NLRP3 inflammasome in these interactions is not yet known; however, MCC950 treatment TBI was found to reduce the extent of blood-brain barrier damage and apoptosis in the acute stages after in TBI mice [70].…”

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…In addition, resveratrol, a natural autophagy inducer, was demonstrated to function in the inhibition of the NLRP3 inflammasome in cerebral cortex through the promotion of sirtuin 1 (SIR1) signaling pathway ( Zou et al, 2018 ). Furthermore, NOX2 was shown to contribute to the progression of traumatic brain injury, and the administration of the NOX2 inhibitors led to the a neuroprotective effect through the suppression of the NLRP3 inflammasome ( Ma et al, 2017 ).…”

Bone marrow derived extracellular vesicles activate osteoclast differentiation in traumatic brain injury induced bone loss

“…In particular, bone resorption and differentiation of osteoclast precursors to mature cells is regulated by the pro-inflammatory transcription factors, NFB, and RANKL [40,41]. Of note, we reported increased chronic inflammatory activation, involving the mobilization of bone marrow derived immune cells, within both blood and brain following a TBI [25,[33][34][35][36]. Consistent with these findings, the key NFB genes, RelA/p65 and Birc3, were dysregulated in the bone marrow Taken together, our study raises the interesting possibility that TBI fosters a chronic proinflammatory state within the bone marrow niche, culminating in increased bone resorption.…”