scholarly journals Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Minako Ito ◽  
Takashi Shichita ◽  
Masahiro Okada ◽  
Ritsuko Komine ◽  
Yoshiko Noguchi ◽  
...  
Keyword(s):  
Brain Injury ◽  
Tyrosine Kinase ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Ischaemic Brain ◽  
Nlrp3 Inflammasome Activation ◽  
Ischaemic Brain Injury

scholarly journals Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

2020 ◽  
Vol 21 (11) ◽  
pp. 3740 ◽  
Author(s):  
Claudia Espinosa-Garcia ◽  
Fahim Atif ◽  
Seema Yousuf ◽  
Iqbal Sayeed ◽  
Gretchen N. Neigh ◽  
...  
Keyword(s):  
Brain Injury ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Global Ischemia ◽  
Inflammasome Activation ◽  
Ischemic Brain Injury ◽  
Primary Microglia ◽  
Ischemic Brain ◽  
Nlrp3 Inflammasome Activation ◽  
The Impact

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
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.

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

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Aijun Zhang ◽  
Youming Lu ◽  
Lei Yuan ◽  
Pengqi Zhang ◽  
Dongdong Zou ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Endothelial Cells ◽  
Brain Injury ◽  
Water Content ◽  
Nlrp3 Inflammasome ◽  
Cell Permeability ◽  
Luciferase Reporter ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

Objective. Inactivation of NLRP3 inflammasome plays a role in reducing the permeability of endothelial cells and improving blood-brain barrier (BBB) dysfunction following traumatic brain injury (TBI). However, the mechanism controlling NLRP3 inflammasome activation remains unclear. This study is aimed at defining the role of miR-29a-5p in NLRP3 inflammasome activation and permeability of endothelial cells under TBI. Methods. The scratch injury model on brain bEnd.3 microvascular endothelial cells was used as in vitro TBI model cells. Effects of miR-29a mimics and inhibitors on TBI model cells were observed by examining their action on FITC, TEER, and protein contents of ZO-1 and occludin, and cell permeability-associated protein. Luciferase reporter assay evaluated miR-29a-5p targeting to NLRP3. ELISA examined of IL-1β and IL-18 levels. miR-29a-5p mimic was injected into TBI mouse and its effect on BBB, indicated by Evans blue (EB) staining assay and cerebral water content, and NLRP3 activation was examined. Results. miR-29a-3p and miR-29a-5p mimics decrease the concentration of FITC, and increase TEER and the protein contents of ZO-1 and occludin in TBI model cells. miR-29a-5p silencing disrupted the permeability of mouse bEnd.3 cells. miR-29a-5p targets to NLRP3 through the binding on its 3 ′ UTR and negatively regulates its expression in TBI model cells. NLRP3 inhibition and miR-29a-5p silencing together caused significantly decreased FITC concentration and increased TEER value and release of IL-1β and IL-18. miR-29a-5p mimic alleviated the BBB and cerebral water content and inactivates NLRP3 in the mouse TBI model. Conclusions. miR-29a-5p mimics protect TBI-induced increased endothelial cell permeability and BBB dysfunction via suppressing NLRP3 expression and activation.

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

PLoS ONE ◽  
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.

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