miR-29a-5p Alleviates Traumatic Brain Injury (TBI)-Induced Permeability Disruption Via Regulating NLRP3 Pathway

Abstract Blood-brain barrier (BBB) dysfunction is presented during traumatic brain injury (TBI) and is dependent upon the activation of the NLRP3/Caspase-1 inflammasome pathway. MicroRNA (miRNA) was proved to inhibit signaling pathway activation by targeting gene expression and we predicated in the database that miR-29a targets to NLRP3. Herein, this study aims to define the regulating role of miR-29a in NLRP3 expression and NLRP3/Caspase-1 inflammasome activation in TBI-induced BBB dysfunction. Our results indicated that miR-29a-5p alleviates TBI-induced the increased permeability of endothelial cell and BBB via suppressing NLRP3 expression and NLRP3/Caspase-1 inflammasome activation, providing a promising strategy for relieving TBI via inhibiting NLRP3/Caspase-1 inflammasome activation.

Download Full-text

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/6057609 ◽

2017 ◽

Vol 2017 ◽

pp. 1-18 ◽

Cited By ~ 32

Author(s):

Merry W. Ma ◽

Jing Wang ◽

Krishnan M. Dhandapani ◽

Darrell W. Brann

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Nadph Oxidase ◽

Nlrp3 Inflammasome ◽

Healing Process ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Nadph Oxidase 2

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.

Download Full-text

Zinc and Traumatic Brain Injury: From Chelation to Supplementation

Medical Sciences ◽

10.3390/medsci8030036 ◽

2020 ◽

Vol 8 (3) ◽

pp. 36 ◽

Cited By ~ 1

Author(s):

Cathy W. Levenson

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Incidence Rate ◽

Molecular Mechanisms ◽

Behavioral Deficits ◽

Zinc Accumulation ◽

Regulated Gene Expression

With a worldwide incidence rate of almost 70 million annually, traumatic brain injury (TBI) is a frequent cause of both disability and death. Our modern understanding of the zinc-regulated neurochemical, cellular, and molecular mechanisms associated with TBI is the result of a continuum of research spanning more than three decades. This review describes the evolution of the field beginning with the initial landmark work on the toxicity of excess neuronal zinc accumulation after injury. It further shows how the field has expanded and shifted to include examination of the cellular pools of zinc after TBI, identification of the role of zinc in TBI-regulated gene expression and neurogenesis, and the use of zinc to prevent cognitive and behavioral deficits associated with brain injury.

Download Full-text

Human Lung Cell Pyroptosis Following Traumatic Brain Injury

Cells ◽

10.3390/cells8010069 ◽

2019 ◽

Vol 8 (1) ◽

pp. 69 ◽

Cited By ~ 4

Author(s):

Nadine Kerr ◽

Juan de Rivero Vaccari ◽

Oliver Umland ◽

M. Bullock ◽

Gregory Conner ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endothelial Cell ◽

Brain Injury ◽

Lung Injury ◽

Critical Role ◽

Gunshot Wounds ◽

Extracellular Vesicle ◽

Inflammasome Activation ◽

Trauma Patients ◽

Severe Tbi

Approximately 30% of traumatic brain injured patients suffer from acute lung injury or acute respiratory distress syndrome. Our previous work revealed that extracellular vesicle (EV)-mediated inflammasome signaling plays a crucial role in the pathophysiology of traumatic brain injury (TBI)-induced lung injury. Here, serum-derived EVs from severe TBI patients were analyzed for particle size, concentration, origin, and levels of the inflammasome component, an apoptosis-associated speck-like protein containing a caspase-recruiting domain (ASC). Serum ASC levels were analyzed from EV obtained from patients that presented lung injury after TBI and compared them to EV obtained from patients that did not show any signs of lung injury. EVs were co-cultured with lung human microvascular endothelial cells (HMVEC-L) to evaluate inflammasome activation and endothelial cell pyroptosis. TBI patients had a significant increase in the number of serum-derived EVs and levels of ASC. Severe TBI patients with lung injury had a significantly higher level of ASC in serum and serum-derived EVs compared to individuals without lung injury. Only EVs isolated from head trauma patients with gunshot wounds were of neural origin. Delivery of serum-derived EVs to HMVEC-L activated the inflammasome and resulted in endothelial cell pyroptosis. Thus, serum-derived EVs and inflammasome proteins play a critical role in the pathogenesis of TBI-induced lung injury, supporting activation of an EV-mediated neural-respiratory inflammasome axis in TBI-induced lung injury.

Download Full-text

Saffron extract attenuates neuroinflammation in rmTBI mouse model by suppressing NLRP3 inflammasome activation via SIRT1

PLoS ONE ◽

10.1371/journal.pone.0257211 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0257211

Author(s):

Mariam J. Shaheen ◽

Amira M. Bekdash ◽

Hana A. Itani ◽

Jamilah M. Borjac

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Neurodegenerative Diseases ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nuclear Factor ◽

Caspase 1 ◽

Nlrp3 Inflammasome Activation ◽

Saffron Extract

Traumatic brain injury (TBI) remains a major cause of morbidity and disability worldwide and a healthcare burden. TBI is an important risk factor for neurodegenerative diseases hallmarked by exacerbated neuroinflammation. Neuroinflammation in the cerebral cortex plays a critical role in secondary injury progression following TBI. The NOD-like receptors (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a key player in initiating the inflammatory response in various central nervous system disorders entailing TBI. This current study aims to investigate the role of NLRP3 in repetitive mild traumatic brain injury (rmTBI) and identify the potential neuroprotective effect of saffron extract in regulating the NLRP3 inflammasome. 24 hours following the final injury, rmTBI causes an upregulation in mRNA levels of NLRP3, caspase-1, the apoptosis-associated speck-like protein containing a CARD (ASC), nuclear factor kappa B (NF-κB), interleukin-1Beta (IL-1β), interleukin 18 (IL-18), nuclear factor erythroid 2–related factor 2 (NRF2) and heme oxygenase 1 (HMOX1). Protein levels of NLRP3, sirtuin 1 (SIRT1), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), and neuronal nuclei (Neu N) also increased after rmTBI. Administration of saffron alleviated the degree of TBI, as evidenced by reducing the neuronal damage, astrocyte, and microglial activation. Pretreatment with saffron inhibited the activation of NLRP3, caspase-1, and ASC concurrent to reduced production of the inflammatory cytokines IL-1β and IL-18. Additionally, saffron extract enhanced SIRT1 expression, NRF2, and HMOX1 upregulation. These results suggest that NLRP3 inflammasome activation and the subsequent inflammatory response in the mice cortex are involved in the process of rmTBI. Saffron blocked the inflammatory response and relieved TBI by activating detoxifying genes and inhibiting NLRP3 activation. The effect of saffron on the NLRP3 inflammasome may be SIRT1 and NF-κB dependent in the rmTBI model. Thus, brain injury biomarkers will help in identifying a potential therapeutic target in treating TBI-induced neurodegenerative diseases.

Download Full-text

MicroRNA Biomarkers in Traumatic Brain Injury

Neurotrauma ◽

10.1093/med/9780190279431.003.0022 ◽

2018 ◽

pp. 261-268

Author(s):

Manish Bhomia ◽

Nagaraja S. Balakathiresan ◽

Kevin K. W. Wang ◽

Barbara Knollmann-Ritschel

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Critical Role ◽

Regulate Gene Expression ◽

Rna Molecules ◽

Posttranscriptional Level ◽

Potential Use ◽

Regulate Gene

Traumatic brain injury (TBI) is currently considered one of the major causes of disability and death worldwide. The cellular and molecular changes of TBI pathology are dynamic and complex in nature. MicroRNAs (miRNA) are small endogenous RNA molecules that regulate gene expression at the posttranscriptional level. Several studies have shown a critical role of miRNAs in the development of long- and short-term TBI pathology. Circulating miRNAs are of great interest as blood-based biomarkers in TBI diagnosis. In this chapter, the authors review recent reports that aim to understand the role of miRNAs in TBI pathophysiology and their potential use as a therapeutic target. Additionally, the authors discuss the potential use of miRNAs as blood-based diagnostic markers for TBI and their possible association with other neurodegenerative diseases.

Download Full-text

Nonessential Role for the NLRP1 Inflammasome Complex in a Murine Model of Traumatic Brain Injury

Mediators of Inflammation ◽

10.1155/2016/6373506 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 31

Author(s):

Thomas Brickler ◽

Kisha Gresham ◽

Armand Meza ◽

Sheryl Coutermarsh-Ott ◽

Tere M. Williams ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cell Death ◽

Brain Injury ◽

Murine Model ◽

Motor Behavior ◽

Interleukin 1 ◽

Inflammasome Activation ◽

Wild Type ◽

Nucleotide Binding Domain

Traumatic brain injury (TBI) elicits the immediate production of proinflammatory cytokines which participate in regulating the immune response. While the mechanisms of adaptive immunity in secondary injury are well characterized, the role of the innate response is unclear. Recently, the NLR inflammasome has been shown to become activated following TBI, causing processing and release of interleukin-1β(IL-1β). The inflammasome is a multiprotein complex consisting of nucleotide-binding domain and leucine-rich repeat containing proteins (NLR), caspase-1, and apoptosis-associated speck-like protein (ASC). ASC is upregulated after TBI and is critical in coupling the proteins during complex formation resulting in IL-1βcleavage. To directly test whether inflammasome activation contributes to acute TBI-induced damage, we assessed IL-1β, IL-18, and IL-6 expression, contusion volume, hippocampal cell death, and motor behavior recovery inNlrp1−/−,Asc−/−, and wild type mice after moderate controlled cortical impact (CCI) injury. Although IL-1βexpression is significantly attenuated in the cortex ofNlrp1−/−andAsc−/−mice following CCI injury, no difference in motor recovery, cell death, or contusion volume is observed compared to wild type. These findings indicate that inflammasome activation does not significantly contribute to acute neural injury in the murine model of moderate CCI injury.

Download Full-text

Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.99 ◽

2012 ◽

Vol 32 (10) ◽

pp. 1939-1947 ◽

Cited By ~ 57

Author(s):

Satoshi Tomura ◽

Juan Pablo de Rivero Vaccari ◽

Robert W Keane ◽

Helen M Bramlett ◽

W Dalton Dietrich

Keyword(s):

Traumatic Brain Injury ◽

Immune Response ◽

Brain Injury ◽

Therapeutic Hypothermia ◽

Innate Immune Response ◽

Cortical Neurons ◽

Purinergic Receptor ◽

Innate Immune ◽

Inflammasome Activation ◽

Caspase 1

Traumatic brain injury (TBI) activates the NALP1/NLRP1 inflammasome, which is an important component of the early innate inflammatory response to injury. We investigated the influence of therapeutic hypothermia on inflammasome activation after TBI. Adult male Sprague–Dawley rats were subjected to moderate fluid percussion brain injury. Temperature manipulation (33°C or 37°C) was initiated 30 minutes after TBI and maintained for 4 hours. At 4 or 24 hours after TBI, traumatized cortex and hippocampus were prepared for immunoblot or immunohistochemical analysis. In the normothermic groups, caspase-1, caspase-11 and expression of the purinergic receptor P2X7 increased at 24 hours after TBI. Posttraumatic hypothermia lead to decreased expression of these proteins at 24 hours compared with normothermic levels. Immunocytochemical studies showed that posttraumatic hypothermia also decreased caspase-1 staining in cerebral cortical neurons compared with normothermic TBI. Cultured cortical neurons subjected to stretch injury demonstrated significant secretion of caspase-1 into the culture medium and caspase-3 activation, both results reduced by hypothermic treatment. Posttraumatic hypothermia decreases inflammasome signaling in neurons and reduces the innate immune response to TBI at 24 hours after injury. Therapeutic hypothermia may protect the injured central nervous system by targeting the detrimental consequences of the innate immune response to injury.

Download Full-text