scholarly journals TSPO Ligands PK11195 and Midazolam Reduce NLRP3 Inflammasome Activation and Proinflammatory Cytokine Release in BV-2 Cells

2020 ◽  
Vol 14 ◽  
Author(s):  
Hao Feng ◽  
Yongxin Liu ◽  
Rui Zhang ◽  
Yingxia Liang ◽  
Lina Sun ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Nlrp3 Inflammasome ◽  
Microglial Activation ◽  
Translocator Protein ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Bv2 Cells ◽  
Translocator Protein 18 Kda ◽  
Inflammatory Effect

Neuroinflammation related to microglial activation plays an important role in neurodegenerative diseases. Translocator protein 18 kDa (TSPO), a biomarker of reactive gliosis, its ligands can reduce neuroinflammation and can be used to treat neurodegenerative diseases. Therefore, we explored whether TSPO ligands exert an anti-inflammatory effect by affecting the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, thereby inhibiting the release of inflammatory cytokines in microglial cells. In the present study, BV-2 cells were exposed to lipopolysaccharide (LPS) for 6 h to induce an inflammatory response. We found that the levels of reactive oxygen species (ROS), NLRP3 inflammasome, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were significantly increased. However, pretreatment with TSPO ligands inhibited BV-2 microglial and NLRP3 inflammasome activation and significantly reduced the levels of ROS, IL-1β, and IL-18. Furthermore, a combination of LPS and ATP was used to activate the NLRP3 inflammasome. Both pretreatment and post-treatment with TSPO ligand can downregulate the activation of NLRP3 inflammasome and IL-1β expression. Finally, we found that TSPO was involved in the regulation of NLRP3 inflammasome with TSPO ligands treatment in TSPO knockdown BV2 cells. Collectively, these results indicate that TSPO ligands are promising targets to control microglial reactivity and neuroinflammatory diseases.

A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation

2016 ◽  
Vol 474 (3) ◽  
pp. 587-593 ◽  
Author(s):  
Ji-Won Lee ◽  
Leah Eunjung Kim ◽  
Hyun-Jung Shim ◽  
Eun-Kyoung Kim ◽  
Won Chan Hwang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Translocator Protein ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Translocator Protein 18 Kda

scholarly journals Role of NLRP3 inflammasome in the development of bladder pain syndrome interstitial cystitis

2019 ◽  
Vol 11 ◽  
pp. 175628721881803 ◽  
Author(s):  
Karol Borys Tudrej ◽  
Tomasz Piecha ◽  
Małgorzata Kozłowska-Wojciechowska
Keyword(s):  
Interstitial Cystitis ◽  
Nlrp3 Inflammasome ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Bladder Epithelium ◽  
Bladder Pain ◽  
Bladder Inflammation ◽  
Nlrp3 Inflammasome Activation

Although it has been proposed that NOD-like receptor protein 3 (NLRP3) inflammasome activation may have an important contribution to the onset of bladder pain syndrome/interstitial cystitis (BPS/IC), as of today there is still insufficient evidence to accept or to reject this hypothesis. However, taking into consideration that inflammasomes have been already shown as important mediators of cyclophosphamide-induced bladder inflammation and that some studies have also revealed human bladder epithelium expresses high levels of NLRP3, such a hypothesis seems to be reasonable. The purpose of this review is to discuss a scenario that NLRP3 inflammasome is a crucial player in the development of this disease. Identification of a novel mediator of bladder inflammation and pain could lead to emerging new therapeutic strategy and the first causative therapy.

scholarly journals NLRP3 inflammasome activation contributes to remifentanil-induced postoperative hyperalgesia via regulation of NMDA receptor NR1 subunit phosphorylation and GLT-1

2020 ◽  
Author(s):  
Yuan Yuan ◽  
Chenxu Wang ◽  
Beibei Dong ◽  
Keliang Xie ◽  
Yonghao Yu
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Nlrp3 Inflammasome ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Remifentanil Infusion ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Behavioural Tests ◽  
Inflammasome Inhibitors

Abstract Background Although remifentanil provides perfect analgesia during operations, postoperative remifentanil-induced hyperalgesia (RIH) might be a challenge to anaesthetists. Increasingly, the NOD-like receptor protein 3 (NLRP3) signalling pathway are being implicated in the initiation and maintenance of these conditions. In the present work, we examined the hypothesis that NLRP3 inflammasome activation contributes to RIH via regulation of NMDA receptor NR1 subunit phosphorylation and glutamate transporter-1 (GLT-1) by interleukin-1β (IL-1β). Methods We first tested the changes in thermal and mechanical hyperalgesia at baseline (24 h before remifentanil infusion) and 2 h, 6 h, 24 h, and 48 h after remifentanil infusion in a rat model of incisional pain. Then, the expression of IL-1β and GLT-1 and phosphorylation of NMDA receptor NR1 subunits (Phospho-NR1) in the L4–L6 spinal cord segments were measured. Furthermore, we investigated the effects of IL-1ra, a selective IL-1β inhibitor, on behavioural tests of RIH and on the expression of GLT-1 and Phospho-NR1. In addition, we measured the expression of TLR4, P2X7R, NLRP3 and caspase-1, which are indicators of NLRP3 inflammasome activation. Finally, we investigated the effects of (+)-naloxone (a TLR4 inhibitor), A438079 (a P2X7R inhibitor) and ac-YVADcmk (a caspase-1 inhibitor), which are all selective NLRP3 inflammasome inhibitors, on behavioural tests of RIH and on the expression of IL-1β, GLT-1 and Phospho-NR1. Results The initiation and maintenance of RIH was mediated by a previously unidentified mechanism--namely, remifentanil-induced spinal NLRP3 inflammasome activation and the associated release of IL-1β. Remifentanil induced significant postoperative hyperalgesia, as indicated by behavioural tests, which were markedly improved by pretreatment with IL-1ra and NLRP3 inflammasome inhibitors. Moreover, remifentanil infusion decreased the expression of GLT-1 and increased Phospho-NR1 in the spinal cord, which were reversed by pretreatment with IL-1ra and NLRP3 inflammasome inhibitors. More importantly, remifentanil infusion increased IL-1β expression and activated NLRP3 inflammasomes, which were significantly attenuated by NLRP3 inflammasome inhibitors. Conclusion The above results suggest that NLRP3 inflammasome activation contributes to RIH via regulation of Phospho-NR1 and GLT-1 by IL-1β. Inhibition of NLRP3 inflammasome activation or IL-1β may be an effective and novel option for the treatment of RIH.

scholarly journals Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Yufei Luo ◽  
Bojun Xiong ◽  
Haiping Liu ◽  
Zehong Chen ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Mechanistic Study ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

scholarly journals Parkin-Dependent Mitophagy is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 897 ◽  
Author(s):  
He ◽  
Li ◽  
Meng ◽  
Wu ◽  
Zhao ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Nissl Staining ◽  
Male Adult ◽  
Cerebral Ischemia Reperfusion ◽  
Nlrp3 Inflammasome Activation

Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial contributor in the inflammatory process during cerebral ischemia/reperfusion (I/R) injury. ATF4 plays a pivotal role in the pathogenesis of cerebral I/R injury, however, its function and underlying mechanism are not fully characterized yet. In the current study, we examined whether ATF4 ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome activation and whether mitophagy is involved in this process. In addition, we explored the role of parkin in ATF4-mediated protective effects. Method: To address these issues, healthy male adult Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1 h followed by 24 h reperfusion. Adeno-associated virus (AAV) and siRNA were injected into rats to overexpress and knockdown ATF4 expression, respectively. After pretreatment with AAV, mdivi-1(mitochondrial division inhibitor-1) was injected into rats to block mitophagy activity. Parkin expression was knockdown using specific siRNA after AAV pretreatment. Result: Data showed that ATF4 overexpression induced by AAV was protective against cerebral I/R injury, as evidenced by reduced cerebral infraction volume, decreased neurological scores and improved outcomes of HE and Nissl staining. In addition, overexpression of ATF4 gene was able to up-regulate Parkin expression, enhance mitophagy activity and inhibit NLRP3 inflammasome-mediated inflammatory response. ATF4 knockdown induced by siRNA resulted in the opposite effects. Furthermore, ATF4-mediated inhibition of NLRP3 inflammasome activation was strongly affected by mitophagy blockage upon mdivi-1 injection. Besides, ATF4-mediated increase of mitophagy activity and inhibition of NLRP3 inflammasome activation were effectively reversed by Parkin knockdown using siRNA. Conclusion: Our study demonstrated that ATF4 is able to alleviate cerebral I/R injury by suppressing NLRP3 inflammasome activation through parkin-dependent mitophagy activity. These results may provide a new strategy to relieve cerebral I/R injury by modulating mitophagy-NLRP3 inflammasome axis.

Mechanism of Ginkgolide B Amelioration of Neuropathic Pain Induced by Chronic Constriction Injury

2021 ◽  
Vol 19 (3) ◽  
pp. 359-365
Author(s):  
Guizhen Yan ◽  
Aobo Ma ◽  
Man Huang ◽  
Yuan Zhang
Keyword(s):  
Neuropathic Pain ◽  
Protein Expression ◽  
Nlrp3 Inflammasome ◽  
Chronic Constriction Injury ◽  
Nerve Fibers ◽  
Fibrous Structure ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Ginkgolide B ◽  
Nlrp3 Inflammasome Activation

Activation of NOD-like receptor protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of neuropathic pain. Ginkgolide B contributes to the suppression of NLRP3 inflammasome activation to prevent hypoxic-ischemic brain injury. However, the role of ginkgolide B on neuropathic pain has not been reported yet. We have shown that administration of ginkgolide B lowered pain threshold measured by paw-withdrawal threshold and paw-withdrawal latency in rats subjected to chronic constriction injury. Nerve fibers in rats postchronic constriction injury were swollen, and the fibrous structure was disordered. Treatment with ginkgolide B attenuated the nerve fiber swelling and reduced the disordered fibrous structure. Ginkgolide B dosage dependently attenuated chronic constriction injury-induced increase of proinflammatory cytokines. Protein expression of NLRP3 and its downstream targets (caspase 1 and IL-1β) were increased by chronic constriction injury and reduced by ginkgolide B. Lastly, ginkgolide B counteracted with the promotive effects of chronic constriction injury on protein expression of TLR4 and p-NF-κB. In conclusion, ginkgolide B demonstrated anti-inflammatory and antinociceptive effects in rats' model with neuropathic pain by suppression of TLR4-NF-κB-mediated NLRP3 inflammasome activation.

FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation

2019 ◽  
Vol 14 (3) ◽  
pp. 478-492 ◽  
Author(s):  
Shu Yao ◽  
Longjun Li ◽  
Xin Sun ◽  
Jun Hua ◽  
Keqi Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Microglial Activation ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation
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