scholarly journals iTRAQ-Based Quantitative Proteomics Indicated Nrf2/OPTN-Mediated Mitophagy Inhibits NLRP3 Inflammasome Activation after Intracerebral Hemorrhage

2021 ◽  
Vol 2021 ◽  
pp. 1-26
Author(s):  
Yijun Cheng ◽  
Mingjian Liu ◽  
Hao Tang ◽  
Bin Chen ◽  
Guoyuan Yang ◽  
...  
Keyword(s):  
Survival Rate ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammasome Activation ◽  
Secondary Brain Injury ◽  
Clear Understanding ◽  
Hematoma Volume ◽  
Nlrp3 Inflammasome Activation

Intracerebral hemorrhage- (ICH-) induced secondary brain injury (SBI) is a very complex pathophysiological process. However, the molecular mechanisms and drug targets of SBI are highly intricate and still elusive, yet a clear understanding is crucial for the treatment of SBI. In the current study, we aimed to confirm that nuclear factor-E2-related factor 2 (Nrf2)/Optineurin- (OPTN-) mediated mitophagy alleviated SBI by inhibiting nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation based on the isobaric tag for relative and absolute quantization (iTRAQ) quantification proteomics. Human ICH brain specimens were collected for iTRAQ-based proteomics analysis. Male Nrf2 wild-type (WT) and knockout (KO) mice were employed to establish ICH murine models. The survival rate, hematoma volume, neurofunctional outcomes, blood-brain barrier (BBB) permeability, brain edema, spatial neuronal death, NLRP3 inflammasome, inflammatory response, mitochondrial function, and mitophagy level were evaluated after ICH. The iTRAQ quantification analysis showed that the differentially expressed proteins (DEPs), Nrf2 and NLRP3, were closely associated with the initiation and development of SBI after ICH. The Nrf2 KO mice had a significantly lower survival rate, bigger hematoma volume, worse neurological deficits, and increased BBB disruption, brain edema, and neuronal death when compared with the Nrf2 WT mice after ICH. Furthermore, Nrf2 KO enhanced NLRP3 inflammasome activation and neuroinflammation as evidenced by the NF-κB activation and various proinflammatory cytokine releases following ICH. Moreover, Nrf2 could interact with and modulate the mitophagy receptor OPTN, further mediating mitophagy to remove dysfunctional mitochondria after ICH. Furthermore, OPTN small interfering RNA (siRNA) increased the NLRP3 inflammasome activation by downregulating mitophagy level and enhancing mitochondrial damage in the Nrf2 WT mice after ICH. Together, our data indicated that Nrf2/OPTN inhibited NLRP3 inflammasome activation, possibly via modulating mitophagy, therefore alleviating SBI after ICH.

Cordycepin confers neuroprotection in mice models of intracerebral hemorrhage via suppressing NLRP3 inflammasome activation

2017 ◽  
Vol 32 (4) ◽  
pp. 1133-1145 ◽  
Author(s):  
Yijun Cheng ◽  
Yongxu Wei ◽  
Wenlei Yang ◽  
Yaying Song ◽  
Hanbing Shang ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Blockage of NLRP3 inflammasome activation ameliorates acute inflammatory injury and long-term cognitive impairment induced by necrotizing enterocolitis in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fangxinxing Zhu ◽  
Lingyu Wang ◽  
Zizhen Gong ◽  
Yanyan Wang ◽  
Yanhong Gao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Survival Rate ◽  
Necrotizing Enterocolitis ◽  
Nlrp3 Inflammasome ◽  
Gastrointestinal Disease ◽  
Brain Inflammation ◽  
Neurological Dysfunction ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

Abstract Background Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease in premature neonates with high mortality and morbidity, while the underlining mechanism of intestinal injury and profound neurological dysfunction remains unclear. Here, we aimed to investigate the involvement of NLPR3 inflammasome activation in NEC-related enterocolitis and neuroinflammation, especially long-term cognitive impairment, meanwhile, explore the protective effect of NLRP3 inhibitor MCC950 on NEC in mice. Methods NLRP3 inflammasome activation in the intestine and brain was assessed in the NEC mouse model, and NLRP3 inhibitor MCC950 was administrated during the development of NEC. Survival rate, histopathological injury of the intestine and brain, and expression of mature IL-1β and other pro-inflammatory cytokines were analyzed. Long-term cognitive impairment was evaluated by behavioral test. Results The expression of NLRP3 and mature IL-1β in the intestine and brain was greatly upregulated in NEC mice compared to the controls. MCC950 treatment efficiently improved NEC survival rate, reduced intestinal and brain inflammation, and ameliorated the severity of pathological damage in both organs. Additionally, in vivo blockage of NLRP3 inflammasome with MCC950 in early life of NEC pups potently protected against NEC-associated long-term cognitive impairment. Conclusions Our findings suggest that NLRP3 inflammasome activation participates in NEC-induced intestinal and brain injury, and early intervention with NLRP3 inhibitor may provide beneficial therapeutic effect on NEC infants.

Silymarin prevents NLRP3 inflammasome activation and protects against intracerebral hemorrhage

2017 ◽  
Vol 93 ◽  
pp. 308-315 ◽  
Author(s):  
Raorao Yuan ◽  
Hengyi Fan ◽  
Shiqi Cheng ◽  
WeiWei Gao ◽  
Xin Xu ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation in Microglia

2021 ◽  
Author(s):  
Yihua He ◽  
Yuan Chang ◽  
Yuqin Peng ◽  
Juan Zhu ◽  
Kewei Liu ◽  
...  
Keyword(s):  
Brain Edema ◽  
Nlrp3 Inflammasome ◽  
Neuroprotective Effect ◽  
Glucose Deprivation ◽  
Inflammasome Activation ◽  
Sham Operation ◽  
Nlrp3 Inflammasome Activation ◽  
Bv2 Cells ◽  
Radiation Induced ◽  
Anti Inflammatory

Abstract Background Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Methods Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. Wild type and Trpm4−/− C57BL/6 male mice underwent radiation-induced brain injury or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats and mice. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, histological examination, and MRI Scanning were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, oxygen-glucose deprivation/reperfusion, or radiation. Results Here, in mice model of radiation-induced brain injury with minimal brain edema, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of radiation-induced microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Likewise, above neuroprotective effects were also confirmed in rat model of cardiac arrest with brain edema combined with neuroinflammation, through preventing SUR1-TRPM4-mediated NLRP3 activation. Of note, the above effects of GLB could be achieved by gene silencing or knockdown of Trpm4. In vitro, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, oxygen-glucose deprivation/reperfusion, or radiation, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca2+ influx, which in turn magnified the K+ efflux via the Na+ influx-driven opening of K+ channels, leading to the NLRP3 inflammasome activation. Conclusions These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K+ efflux and promotes NLRP3 inflammasome activation.

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