scholarly journals NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1β-mediated neuroinflammation

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Zi-Teng Zhang ◽  
Xiao-Lei Gu ◽  
Xin Zhao ◽  
Xian He ◽  
Hao-Wei Shi ◽  
...  
Keyword(s):  
Heat Tolerance ◽  
Knockout Mice ◽  
Nlrp3 Inflammasome ◽  
Heat Stroke ◽  
Heat Exposure ◽  
Neutralizing Antibody ◽  
Underlying Mechanism ◽  
Stroke Severity ◽  
Inflammasome Activation ◽  
Prior Infection

Abstract Background Patients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke. Methods In this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1β neutralizing antibody was injected to test potential therapeutic effect on heat stroke. Results Prior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1β in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1β production with prior infection condition. Furthermore, IL-1β neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke. Conclusions Based on the above results, NLRP3/IL-1β induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1β may serve as a biomarker for heat stroke severity and potential therapeutic method.

NLRP3 ablation enhances heat tolerance in endotoxemic mice by inhibiting IL-1β-mediated neuroinflammation

2020 ◽  
Author(s):  
Zi-Teng Zhang ◽  
Xiao-Lei Gu ◽  
Xin Zhao ◽  
Yiming Zhang ◽  
Yanzhou Song ◽  
...  
Keyword(s):  
Heat Tolerance ◽  
Nlrp3 Inflammasome ◽  
Heat Stroke ◽  
Neutralizing Antibody ◽  
Inflammasome Activation ◽  
Knock Out ◽  
Nlrp3 Inflammasome Activation ◽  
Knock Out Mice

Abstract Background: Patients with pre-existing illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke. Methods: In this study, we exposed primary murine peritoneal macrophages to different temperature and time length combinations with and without lipopolysaccharide (LPS: 20ng/mL). Cell viability, lactate dehydrogenase (LDH) and pro-inflammatory cytokine were measured. We also established heat stroke mice model with preexisting endotoxemia (LPS: 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. In vitro, NLRP3 inflammasome activation was measured in vitro by using Real-time PCR and Western blot. In vivo, mice hypothalamus was dissected and NLRP3 inflammasome activation was also explored. To further demonstrate the participation of NLRP3 inflammasome, Nlrp3 knock out mice were used. In addition, IL-1β neutralizing antibody was injected to test whether its effect on heat stroke induce injury. Results: LPS administration was found to exacerbate macrophage damage and heat stroke-induced injury in mice. LPS administration also intensively activated NLRP3 inflammasome and increased the production of IL-1β and Caspase-1 p10 in heat stroke group both in vitro and in vivo. Nlrp3 knockout protected peritoneal macrophage from LPS/heat treatment and reduced IL-1β release in primary mice macrophages in vitro. The use of Nlrp3 knock out mice further enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1β production in given heat stroke condition. Furthermore, IL-1β neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke. Conclusions: Based on the above results, we concluded that the NLRP3 inflammasome mediates the exacerbation of heat stroke-induced injury in preexisting endotoxemia, and antagonizing NLRP3 inflammasome activity might be a potential strategy for the treatment of heat stroke in vulnerable population.

scholarly journals Irisin Contributes to the Hepatoprotection of Dexmedetomidine during Intestinal Ischemia/Reperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Xin Fan ◽  
Juan Du ◽  
Mao-Hua Wang ◽  
Jia-Man Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Inflammasome Activation ◽  
High Morbidity ◽  
Antibody Treatment ◽  
Sod Activity ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia/reperfusion (I/R), which is associated with high morbidity and mortality, is also accompanied with abnormal energy metabolism and liver injury. Irisin, a novel exercise-induced hormone, can regulate adipose browning and thermogenesis. The following study investigated the potential role of dexmedetomidine in liver injury during intestinal I/R in rats. Adult male Sprague–Dawley rats underwent occlusion of the superior mesenteric artery for 90 min followed by 2 h of reperfusion. Dexmedetomidine or irisin-neutralizing antibody was intravenously administered for 1 h before surgery. The results demonstrated that severe intestine and liver injuries occurred during intestinal I/R as evidenced by pathological scores and an apparent increase in serum diamine oxidase (DAO), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels. In addition, the hepatic irisin, cleaved caspase-3, Bax, and NLRP3 inflammasome components (including NLRP3, ASC, and caspase-1), protein expressions, apoptotic index, reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 6 levels increased; however, the serum irisin level and hepatic Bcl-2 protein expression and superoxide dismutase (SOD) activity decreased after intestinal I/R. Interestingly, dexmedetomidine could reduce the above listed changes and increase the irisin levels in plasma and the liver in I/R rats. Dexmedetomidine-mediated protective effects on liver injury and NLRP3 inflammasome activation during intestinal I/R were partially abrogated via irisin-neutralizing antibody treatment. The results suggest that irisin might contribute to the hepatoprotection of dexmedetomidine during intestinal ischemia/reperfusion.

Pre-existing inflammatory state compromises heat tolerance in rats exposed to heat stress

2007 ◽  
Vol 292 (1) ◽  
pp. R186-R194 ◽  
Author(s):  
Chin Leong Lim ◽  
Gary Wilson ◽  
Lindsay Brown ◽  
Jeff S. Coombes ◽  
Laurel T. Mackinnon
Keyword(s):  
Heat Stress ◽  
Heat Tolerance ◽  
Tissue Damage ◽  
Wistar Rats ◽  
Heat Stroke ◽  
Heat Exposure ◽  
The Core ◽  
Male Wistar Rats ◽  
Inflammatory State ◽  
Severe Heat Stress

This study investigated the roles of endotoxemia and heat-induced tissue damage in the pathology of heat stroke. In groups of eight, male Wistar rats were treated with heat exposure only (HE), or heat exposure with turpentine (T+HE), dexamethasone (D+HE), and turpentine and dexamethasone combined (TD+HE). The rats remained sedated for 2 h after receiving the respective treatments, followed by heat exposure until the core temperature (Tc) was 42°C for 15 min; control rats received turpentine (T), dexamethasone (D), and turpentine and dexamethasone (TD) without heat stress. Blood samples were collected before treatment ( baseline I), after 2 h of passive rest ( baseline II), at Tc 40°C (T40), and 15 min after achieving Tc 42°C (T42). No rats died in the nonheat-stressed groups. Survival rate was lowest in the TD+HE rats (37.5%), followed by the HE (62.5%), T+HE (75%), and D+HE (100%) rats ( P < 0.05). The duration of survival at T42°C was shortest in the TD+HE rats (9.9 ± 6.2 min) ( P < 0.01), followed by the T+HE (11.3 ± 6.1 min) and the HE (12.2 ± 4 min) ( P < 0.05) rats. The increase in plasma IL-6 concentrations was highest in the T+HE (352%) and HE (178%) rats ( P < 0.05). D+HE treatment suppressed the increases in plasma aspartate transaminase, alanine aminotransferase, and IL-6 and LPS concentrations during severe heat stress. Heat stroke can be triggered by endotoxemia or heat-induced tissue damage, and preexisting inflammation compromises heat tolerance, whereas blocking endotoxemia increases heat tolerance.

Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis

Nanoscale ◽  
2018 ◽  
Vol 10 (19) ◽  
pp. 9141-9152 ◽  
Author(s):  
Xuyao Zhang ◽  
Jingyun Luan ◽  
Wei Chen ◽  
Jiajun Fan ◽  
Yanyang Nan ◽  
...  
Keyword(s):  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Nlrp3 Inflammasome ◽  
Mesoporous Silica Nanoparticles ◽  
Silica Nanoparticle ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Mesoporous Silica Nanoparticle ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Novel insights into mesoporous silica nanoparticle (MSN)-induced hepatotoxicity and the underlying mechanism, facilitating an increase of the biosafety of MSNs.

A Single Heat Exposure Improves Heat Tolerance in a Mouse Exertional Heat Stroke Model

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Jermaine Allen Ward ◽  
Shauna Dineen ◽  
Mark Plamper ◽  
Thomas Mayer ◽  
Lisa Leon
Keyword(s):  
Heat Tolerance ◽  
Heat Stroke ◽  
Heat Exposure ◽  
Stroke Model ◽  
Exertional Heat Stroke

Increasing Autophagy ameliorate all-trans-retinal-activated NLRP3 Inflammasome 2 in human THP-1 macrophage cells

2021 ◽  
Author(s):  
Qingqing Xia ◽  
Lvxing Huang ◽  
Hengyi Chen ◽  
Yingying Zhou ◽  
Lingmin Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Innate Immune ◽  
Cell Counting ◽  
Autophagic Flux ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Related Proteins ◽  
Excessive Activation ◽  
Insight Into

Abstract BackgroundProfound inflammation that mediated by innate immune sensors can be observed in retina, and is considered to play an important role in the pathogenesis of all-trans-retinal (atRAL)-caused retinal degeneration. However, the underlying mechanism remains elusive. MethodsCell viability was detected with Cell Counting Kit-8 (CCK-8). The concentration of IL-1β was evaluated using IL-1β ELISA Kits. The levels of autophagy-related proteins were measured by Western blotting. The measurement of autophagic flux was performed with virus vectors packing tandem monomeric mCherry-eGFP-tagged LC3B. ResultsWe focused on studying the effects of atRAL on macrophage cell line THP-1 and determining the underlying signal pathway through pharmacological and genetical manipulation. We first found the maturation and release of IL-1β was regulated by the activation of NLRP3 inflammasome. We secondly found that mitochondria-associated reactive oxygen species (ROS) were involved in the regulation of NLRP3 inflammasome activation and caspase 1 cleavage. Finally, we found that atRAL functionally activated autophagy in THP-1 cells, and atRAL-caused NLRP3 inflammasome activation is suppressed by autophagy. Overall, our results show atRAL simultaneously activates NLRP3 inflammasome and autophagy in THP-1 cells, and increasing autophagy leads to the inhibition of the excessive activation of NLRP3 inflammasome. Our study provides new insight into the pathogenesis of aging related retina degeneration.

scholarly journals CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Youjia Fan ◽  
Gaici Xue ◽  
Qianbo Chen ◽  
Ye Lu ◽  
Rong Dong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Pain ◽  
Analgesic Effect ◽  
Pain Treatment ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Relieve Pain ◽  
Nlrp3 Inflammasome Activation ◽  
Key Factor ◽  
Nlrp3 Inflammasomes

Peripheral tissue damage leads to inflammatory pain, and inflammatory cytokine releasing is the key factor for inducing the sensitization of nociceptors. As a calcium ion channel, TRPA1 plays an important role in pain and inflammation, thus becoming a new type of anti-inflammatory and analgesic target. However, there is no consensus on the role of this channel in mechanical hyperalgesia caused by inflammation. Here, we aim to explore the role and underlying mechanism of the inflammasome inhibitor CY-09 in two classic inflammatory pain models. We evaluated pain behavior on animal models, cytokine levels, intracellular Ca2+ levels, transient TRPA1 expression, NF-κB transcription, and NLPR3 inflammasome activation. Consistently, CY-09 reduced the production of inflammatory cytokines, intracellular Ca2+ levels, and the activation of TRPA1 by inhibiting the activation of inflammasomes, thereby reducing the proinflammatory polarization of macrophages and alleviating animal pain and injury. Importantly, AITC (TRPA1 agonist) significantly reversed the analgesic effect of CY-09, indicating that TRPA1 was involved in the analgesic effect of CY-09. Our findings indicate that CY-09 relieves inflammation and pain via inhibiting TRPA1-mediated activation of NLRP3 inflammasomes. Thus, NLRP3 inflammasome may be a potential therapeutic target for pain treatment and CY-09 may be a pharmacological agent to relieve inflammatory pain, which needs further research.

scholarly journals Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

2020 ◽  
Author(s):  
Jianjun Jiang ◽  
Jin Yang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Acid Sphingomyelinase ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Abstract Background: The NOD-Like Receptor Protein 3 (NLRP3) inflammasome is a crucial component of an array of inflammatory conditions. It functions by boosting the secretion of pro-inflammatory cytokines: interleukin-1β (IL-1β) and interleukin-18 (IL-18). Previous studies have established the vital role of the acid sphingomyelinase (ASM)/ceramide (Cer) pathway in the functional outcome of cells, with a particular emphasis on the inflammatory processes. This study aimed to explore the effects and associated underlying mechanism of Cer-induced NLRP3 inflammasome activation.Methods: Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells was used as an in vitro inflammatory model. Western blotting and Real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were evaluated using ELISA kits. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content.Results: Imipramine, a well-known inhibitor of ASM, significantly inhibited ASM activity and inhibited Cer accumulation, which indicated ASM activation. Besides, it also suppressed the LPS/ATP-induced expression of proteins and mRNA: thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β and IL-18. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced TXNIP/NLRP3 inflammasome activation; however, it did not affect LPS/ATP-induced ASM activation and ceramide production. Further analysis showed that the exogenous C2-Cer treated J774A.1 cells induced the overexpression of TXNIP, NLRP3, caspase-1, IL-1β and IL-18. Besides, TXNIP siRNA or verapamil inhibited C2-Cer-induced TXNIP overexpression and NLRP3 inflammasome activation.Conclusion: This study demonstrated the involvement of the ASM/Cer/TXNIP signaling pathway in NLRP3 inflammasome activation.

scholarly journals NLRP3 inflammasome activation mediates sleep deprivation-induced pyroptosis in mice

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11609
Author(s):  
Kun Fan ◽  
Jiajun Yang ◽  
Wen-Yi Gong ◽  
Yong-Chao Pan ◽  
Peibing Zheng ◽  
...  
Keyword(s):  
Sleep Deprivation ◽  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Inflammasome Activation ◽  
Pcr Array ◽  
Mice Model ◽  
Rt Pcr ◽  
Array Data ◽  
Ca1 Region

Background Sleep deprivation (SD) has many deleterious health effects, including cognitive decline, work ability decline, inadequate alertness, etc. Neuroinflammation plays an important role in sleep deprivation. However, the underlying mechanism is still unclear. Methods In the present study, we detected the activation of microglia and apoptosis of nerve cells in sleep deprivation (SD) mice model using IHC, HE staining and TUNEL apoptosis assay. RT-PCR array data were used to detect the expression of inflammatory bodies in hippocampal CA1 region after sleep deprivation, to explore how NLRP3 inflammasome regulates neuronal apoptosis and how specific signaling pathways are involved in SD-induced activation of NLRP3/pyrosis axis. Results We found the number of microglia significantly increased in SD mice, while this effect was blocked by sleep recovery. RT-PCR array data suggested that NLRP3 inflammasome, but not other inflammasomes, was obviously increased in hippocampus CA1 region after sleep deprivation. Mechanistically, we found that NLRP3 mediated the pyroptosis of neurocyte through GSDMD-dependent way , and P38 and ERK-MAPK signaling pathway is involved in SD-induced activation of NLRP3/pyroptosis axis. All these results suggested that MAPK/NLRP3 axis mediated SD-induced pyroptosis. Conclusion NLRP3 plays an important role in SD-induced neuroinflammation. Thus, NLRP3 inflammasome is expected to be a potential therapeutic target for SD-induced neuroinflammation.

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