GPR40 agonist inhibits NLRP3 inflammasome activation via modulation of nuclear factor-κB and sarco/endoplasmic reticulum Ca2+-ATPase

Cerebrovascular diseases are pathological conditions involving impaired blood flow in the brain, primarily including ischaemic stroke, intracranial haemorrhage, and subarachnoid haemorrhage. The nucleotide-binding and oligomerisation (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a protein complex and a vital component of the immune system. Emerging evidence has indicated that the NLRP3 inflammasome plays an important role in cerebrovascular diseases. The function of the NLRP3 inflammasome in the pathogenesis of cerebrovascular diseases remains an interesting field of research. In this review, we first summarised the pathological mechanism of cerebrovascular diseases and the pathological mechanism of the NLRP3 inflammasome in aggravating atherosclerosis and cerebrovascular diseases. Second, we outlined signalling pathways through which the NLRP3 inflammasome participates in aggravating or mitigating cerebrovascular diseases. Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome; activation of the NLRP3 inflammasome can aggravate cerebrovascular diseases by mediating apoptosis and pyroptosis. Autophagy/mitochondrial autophagy, nuclear factor E2-related factor-2 (Nrf2), interferon (IFN)-β, sirtuin (SIRT), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) reportedly alleviate cerebrovascular diseases by inhibiting NLRP3 inflammasome activation. Finally, we explored specific inhibitors of the NLRP3 inflammasome based on the two-step activation of the NLRP3 inflammasome, which can be developed as new drugs to treat cerebrovascular diseases.

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

Lipids in Health and Disease ◽

10.1186/s12944-021-01446-4 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Jianjun Jiang ◽

Yining Shi ◽

Jiyu Cao ◽

Youjin Lu ◽

Gengyun Sun ◽

...

Keyword(s):

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Mrna Level ◽

Scavenger Receptor ◽

Nuclear Factor Κb ◽

Inflammasome Activation ◽

Mrna Levels ◽

Irreversible Inhibitor ◽

Nlrp3 Inflammasome Activation

Abstract Background This study aimed to explore the effects of ceramide (Cer) on NLRP3 inflammasome activation and their underlying mechanisms. Methods Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells and THP-1 macrophages was used as an in vitro model of inflammation. 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 measured by ELISA. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content. Results Imipramine, a well-known inhibitor of ASM, significantly inhibited LPS/ATP-induced activity of ASM and the consequent accumulation of Cer. Additionally, imipramine suppressed the LPS/ATP-induced expression of thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β, and IL-18 at the protein and mRNA level. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced activation of TXNIP/NLRP3 inflammasome but did not affect LPS/ATP-induced ASM activation and Cer formation. TXNIP siRNA and verapamil inhibited C2-Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome. In addition, the pretreatment of cells with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked Cer-induced upregulation of nuclear factor-κB (NF-κB) activity, TXNIP expression, and NLRP3 inflammasome activation. Inhibition of NF-κB activation by SN50 prevented Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome but did not affect CD36 expression. Conclusion This study demonstrated that the ASM/Cer/TXNIP signaling pathway is involved in NLRP3 inflammasome activation. The results documented that the CD36-dependent NF-κB-TXNIP signaling pathway plays an essential role in the Cer-induced activation of NLRP3 inflammasomes in macrophages.

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The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽

10.3390/cells9051219 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1219 ◽

Cited By ~ 3

Author(s):

Yang Zhou ◽

Zhizi Tong ◽

Songhong Jiang ◽

Wenyan Zheng ◽

Jianjun Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Immune Defense ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Cholesterol Trafficking ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

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Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner

Pharmacological Research ◽

10.1016/j.phrs.2015.05.012 ◽

2015 ◽

Vol 99 ◽

pp. 101-115 ◽

Cited By ~ 53

Author(s):

Yi Li ◽

Jie Yang ◽

Mei-Hong Chen ◽

Qiang Wang ◽

Min-Jian Qin ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Endoplasmic Reticulum Stress ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Dependent Manner ◽

Nlrp3 Inflammasome Activation

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Anisodamine inhibits endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in rhabdomyolysis-induced acute kidney injury

APOPTOSIS ◽

10.1007/s10495-017-1414-y ◽

2017 ◽

Vol 22 (12) ◽

pp. 1524-1531 ◽

Cited By ~ 10

Author(s):

Xiaopeng Yuan ◽

Yitao Zheng ◽

Chuanbao Chen ◽

Changxi Wang

Keyword(s):

Acute Kidney Injury ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Nlrp3 Inflammasome ◽

Kidney Injury ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Burn Plus Lipopolysaccharide Augments Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation and Reduces PGC-1α in Liver

Shock ◽

10.1097/shk.0000000000000075 ◽

2014 ◽

Vol 41 (2) ◽

pp. 138-144 ◽

Cited By ~ 28

Author(s):

Li Diao ◽

Alexandra H. Marshall ◽

Xiaojing Dai ◽

Elena Bogdanovic ◽

Abdikarim Abdullahi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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BAY 11-7082 inhibits the NF-κB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis

Clinical Science ◽

10.1042/cs20160645 ◽

2017 ◽

Vol 131 (6) ◽

pp. 487-498 ◽

Cited By ~ 29

Author(s):

Natasha Irrera ◽

Mario Vaccaro ◽

Alessandra Bitto ◽

Giovanni Pallio ◽

Gabriele Pizzino ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Nuclear Translocation ◽

Nuclear Factor Κb ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Dermal Thickness ◽

Nlrp3 Inflammasome Activation ◽

Histological Score ◽

Interesting Approach ◽

Factor Α

BAY 11-7082 antagonizes I-κB kinase-β preventing nuclear translocation of nuclear factor-κB (NF-κB); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-κB is involved in psoriasis, whereas the role of NLRP3 is controversial. We investigated BAY 11-7082 effects in an experimental model of psoriasis-like dermatitis. Psoriasis-like lesions were induced by a topical application of imiquimod (IMQ) cream (62.5 mg/day) on the shaved back skin of C57BL/6 and NLRP3 knockout (KO) mice for 7 consecutive days. Sham psoriasis animals were challenged with Vaseline cream. Sham and IMQ animals were randomized to receive BAY 11-7082 (20 mg/kg/i.p.) or its vehicle (100 μl/i.p of 0.9% NaCl). Skin of IMQ animals developed erythema, scales, thickening and epidermal acanthosis. IMQ skin samples showed increased expression of pNF-κB and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF-κB, NLRP3, tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β expression, blunted the phosphorylation of signal transducer and activators of transcription 3 (STAT3) and decreased IL-23 levels. In addition, BAY 11-7082 reawakened the apoptotic machinery. NLRP3 KO animals showed a reduced total histological score but persistent mild acanthosis, dermal thickness and expression of pNF-κB and pSTAT3, following IMQ application. Our data suggest that BAY 11-7082 might represent an interesting approach for the management of psoriasis-like dermatitis depending on the dual inhibition of NF-κB and NLRP3.

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