Baicalein attenuates α-synuclein aggregation, inflammasome activation and autophagy in the MPP+-treated nigrostriatal dopaminergic system in vivo

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

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The Role of Melatonin on NLRP3 Inflammasome Activation in Diseases

Antioxidants ◽

10.3390/antiox10071020 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1020

Author(s):

Burak Ibrahim Arioz ◽

Emre Tarakcioglu ◽

Melis Olcum ◽

Sermin Genc

Keyword(s):

Nlrp3 Inflammasome ◽

Intracellular Signaling ◽

Metabolic Diseases ◽

Metabolic Stress ◽

Clinical Importance ◽

Rapid Identification ◽

In Vivo Studies ◽

Inflammasome Activation

NLRP3 inflammasome is a part of the innate immune system and responsible for the rapid identification and eradication of pathogenic microbes, metabolic stress products, reactive oxygen species, and other exogenous agents. NLRP3 inflammasome is overactivated in several neurodegenerative, cardiac, pulmonary, and metabolic diseases. Therefore, suppression of inflammasome activation is of utmost clinical importance. Melatonin is a ubiquitous hormone mainly produced in the pineal gland with circadian rhythm regulatory, antioxidant, and immunomodulatory functions. Melatonin is a natural product and safer than most chemicals to use for medicinal purposes. Many in vitro and in vivo studies have proved that melatonin alleviates NLRP3 inflammasome activity via various intracellular signaling pathways. In this review, the effect of melatonin on the NLRP3 inflammasome in the context of diseases will be discussed.

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Pharmacological Blocker of NF-κb and Mitochondrial Ros Restrict NLRP3 Inflammasome Activation and Rescue Dopaminergic Neurons in Vitro and in Vivo Parkinson’s Disease

10.21203/rs.3.rs-260478/v1 ◽

2021 ◽

Author(s):

Sahabuddin Ahmed ◽

Samir Ranjan Panda ◽

Mohit Kwatra ◽

Bidya Dhar Sahu ◽

VGM Naidu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Free Radicals ◽

Nlrp3 Inflammasome ◽

Nuclear Translocation ◽

Inflammasome Activation ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation

Abstract Several activators of NLRP3 inflammasome have been described; however, the central mechanisms of NLRP3 inflammasome activation in brain microglia, especially at the activating step through free radical generation, still require further clarification. Hence the present study aimed to investigate the role of free radicals in activating NLRP3 inflammasome driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in vitro and in vivo models of Parkinson’s disease. Initial priming of microglial cells with lipopolysaccharide (LPS) following treatment with hydrogen peroxide (H2O2) induces NF-κB translocation to nucleus with robust generation of free radicals that act as Signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses nuclear translocation of NF-κB and maintains cellular redox homeostasis in microglia that limits NLRP3 inflammasome activation along with processing active caspase-1, IL-1β and IL-18. To further correlates the in vitro study with in vivo MPTP model, treatment with PA also inhibits the nuclear translocation of NF-κB and downregulates the NLRP3 inflammasome activation. PA administration upregulates various antioxidant enzymes levels and restored the level of dopamine and other neurotransmitters in the striatum of the mice brain with improved behavioural activities. Additionally, treatment with Mito-TEMPO (a mitochondrial ROS inhibitor) was also seen to inhibit NLRP3 inflammasome and rescue dopaminergic neuron loss in the mice brain. Therefore, we conclude that NLRP3 inflammasome activation requires a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting NLRP3 inflammasome pathway in Parkinson’s disease.

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Abstract P259: Endothelial Acid Sphingomyelinase Gene Determines Inflammasome Activation and Atherosclerotic Lesions in Carotid Arteries During Hypercholesterolemia

Hypertension ◽

10.1161/hyp.66.suppl_1.p259 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Min Xia ◽

Krishna M Bioni ◽

Yang Chen ◽

Xiang Li ◽

Ashley L Pitzer ◽

...

Keyword(s):

Carotid Arteries ◽

Acid Sphingomyelinase ◽

Receptor Protein ◽

Inflammasome Activation ◽

Neointimal Formation ◽

Atherosclerotic Lesions ◽

Junction Protein ◽

Nlrp3 Inflammasomes

Nucleotide oligomerization domain (NOD)-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasome has been reported to be activated by atherogenic factors, thereby triggering endothelial injury and consequent atherosclerotic lesions in the arterial wall. However, the mechanism activating and regulating Nlrp3 inflammasomes remains poorly understood. The present study tested whether membrane raft (MR) signaling platforms associated with acid sphingomyelinase (ASM) and its product ceramide (Ce) importantly contribute to the activation of Nlrp3 inflammasomes and atherosclerotic lesions during hypercholesterolemia (HC). By confocal microscopy and biochemical analyses, we demonstrated the formation and activation of Nlrp3 inflammasomes in the intima of the carotid arteries of Asm +/+ mice with HC (as shown by a 2-fold increase in caspase-1 activity and a 6-fold enhancement of IL-1β positive stain areas), but not in Asm -/- mice. In endothelium-specific ASM transgenic mice (EC-Asm trg ), this inflammasome formation and activation were enhanced. Correspondingly, HC-induced increases in IL-1β production, ASM expression, Ce level and MR-gp91 phox clustering in the carotid intima were abolished in Asm -/- mice, but enhanced in EC-Asm trg mice. Functionally, endothelium-dependent vasodilation (EDVD) in carotid arteries in vivo (by ultrasound flowmetry) and in vitro (in perfused artery) was impaired by HC in Asm +/+ mice by 33% and 54%, respectively. This endothelial dysfunction was not observed in Asm -/- mice. The endothelial tight junction protein, ZO-1 was reduced by HC in both Asm +/+ and EC-Asm trg mice, but not in Asm -/- mice. It was also found that HC-increased neointimal formation, T-cell infiltration, and fibrosis in 2-week partially ligated carotid arteries (PLCA) occurred in Asm +/+ mice, but not in Asm -/- mice with HC. EC-Asm trg mice even exhibited more severe inflammatory and atherosclerotic lesions. All these results suggest that Asm gene and related MR clustering are essential to endothelial inflammasome activation and dysfunction in carotid arteries, ultimately determining the extent of atherosclerotic lesions.

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Kaempferol Alleviates Corneal Transplantation Rejection by Inhibiting NLRP3 Inflammasome Activation and Macrophage M1 Polarization via Promoting Autophagy

10.21203/rs.3.rs-368448/v1 ◽

2021 ◽

Author(s):

Huiwen Tian ◽

Shumei Lin ◽

Jing Wu ◽

Ming Ma ◽

Jian Yu ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Macrophage Polarization ◽

Corneal Transplantation ◽

Inflammasome Activation ◽

M1 Polarization ◽

Nlrp3 Inflammasome Activation ◽

M1 Macrophage ◽

Transplantation Rejection

Abstract Corneal transplantation rejection remains a major threat to the success rate in high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural flavonoid that has been proven in various studies to possess anti-inflammatory, antioxidant, anticancer, and neuroprotective properties. However, the relationship between kaempferol and corneal transplantation remains largely unexplored. To address this, both in vivo and in vitro, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced inflammatory model in THP-1 derived human macrophages. In the transplantation experiments, we observed an enhancement in the NLRP3 / IL-1 β axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the inflammatory model, we found that different concentrations of kaempferol can reduce the LPS-induced M1 polarization and NLRP3 inflammasome activation. Moreover, we confirmed that kaempferol induced autophagy and that autophagy inhibitors reversed the effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of the NLRP3 inflammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol could be used as a potential therapeutic agent in the treatment of allograft rejection.

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ASC deglutathionylation is a checkpoint for NLRP3 inflammasome activation

Journal of Experimental Medicine ◽

10.1084/jem.20202637 ◽

2021 ◽

Vol 218 (9) ◽

Author(s):

Shuhang Li ◽

Linlin Wang ◽

Zhihao Xu ◽

Yuanyuan Huang ◽

Rufeng Xue ◽

...

Keyword(s):

Metabolic Control ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation ◽

Multiple Molecules ◽

Excessive Activation

Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASCC171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, AscC171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.

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The Essential Oil of Artemisia argyi H.Lév. and Vaniot Attenuates NLRP3 Inflammasome Activation in THP-1 Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.712907 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pengxiao Chen ◽

Qi Bai ◽

Yanting Wu ◽

Qiongzhen Zeng ◽

Xiaowei Song ◽

...

Keyword(s):

Essential Oil ◽

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Inflammasome Activation ◽

Caspase 1 ◽

Artemisia Argyi ◽

Nlrp3 Inflammasome Activation ◽

Long Time

Artemisia argyi H. Lév. and Vaniot is a traditional medical herb that has been used for a long time in China and other Asian counties. Essential oil is the main active fraction of Artemisia argyi H. Lév. and Vaniot, and its anti-inflammatory potential has been observed in vitro and in vivo. Here, we found that the essential oil of Artemisia argyi H. Lév. and Vaniot (EOAA) inhibited monosodium urate (MSU)- and nigericin-induced NLRP3 inflammasome activation. EOAA suppressed caspase-1 and IL-1β processing and pyroptosis. NF-κB p65 phosphorylation and translocation were also inhibited. In addition, EOAA suppressed nigericin-induced NLRP3 inflammasome activation without blocking ASC oligomerization, suggesting that it may inhibit NLRP3 inflammasome activation by preventing caspase-1 processing. Our study thus indicates that EOAA inhibits NLRP3 inflammasome activation and has therapeutic potential against NLRP3-driven diseases.

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Vaspin Alleviates Osteoarthritis by Inhibiting NLRP3-mediated Inflammation

10.21203/rs.3.rs-285169/v1 ◽

2021 ◽

Author(s):

Xianjie Zhu ◽

Shiyou Dai ◽

Baohua Xia ◽

Jianbao Gong ◽

Bingzheng Ma

Keyword(s):

Nlrp3 Inflammasome ◽

Wistar Rat ◽

Cartilage Degradation ◽

Pathological Process ◽

Inflammasome Activation ◽

Protective Effects ◽

Collagen Formation ◽

Nlrp3 Inflammasome Activation

Abstract Background:Osteoarthritis (OA) is a chronic degenerative joint bone disease characterized by cartilage degradation. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is associated with the inflammatory and metabolic responses to OA. However, the underlying mechanisms of the pathological process of OA are not clear. The aim of the present study was to examine the protective effects of vaspin both in vitro and in vivo.Methods:Monosodium iodoacetate (MIA)-induced Wistar rat model of OA was used to assess the in vivo effects of vaspin administered for 12 weeks. The characteristics of OA were evaluated by haematoxylin and eosin (H&E) and safranin O/fast green staining. The anti-inflammatory effect of vaspin was assessed using immunohistochemical, qRT-PCR, and western blotting analysis. Parallel experiments to detect the molecular mechanism through which vaspin prevents OA were performed using LPS-treated chondrocytes.Results:Our results showed that the degeneration of cartilage and upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-13 were ameliorated by vaspin. Additionally, vaspin suppressed the activation of TXNIP/NLRP3 and secretion of tumor necrosis factor ɑ and interleukin-1β in vivo. It was further confirmed that vaspin could also suppress LPS-induced NLRP3 inflammasome activation and reduce collagen formation in chondrocytes. Moreover, vaspin inhibited NLRP3 inflammasome activation by suppressing the ROS/TXNIP pathway.Conclusions: Vaspin inhibited OA by repressing TXNIP/NLRP3 activation in in vitro and in vivo models of OA, thus providing a novel therapeutic strategy for OA.

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Optogenetic activation of spinal microglia triggers chronic pain in mice

PLoS Biology ◽

10.1371/journal.pbio.3001154 ◽

2021 ◽

Vol 19 (3) ◽

pp. e3001154

Author(s):

Min-Hee Yi ◽

Yong U. Liu ◽

Anthony D. Umpierre ◽

Tingjun Chen ◽

Yanlu Ying ◽

...

Keyword(s):

Chronic Pain ◽

Microglial Activation ◽

Red Light ◽

Inflammasome Activation ◽

Pain Hypersensitivity ◽

Microglial Phenotype ◽

C Fiber ◽

Inward Currents ◽

Calcium Elevation

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been any direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1β production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

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