scholarly journals S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1706
Author(s):  
Chi-Ho Lee ◽  
Ji Woong Choi
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Receptor Subtype ◽  
Inflammasome Activation ◽  
Mouse Bone Marrow ◽  
Nlrp3 Inflammasome Activation ◽  
Key Factor ◽  
Signaling Axis ◽  
Sphingosine 1 Phosphate ◽  
Effector Pathways

The activation of NLRP3 inflammasome is a key factor for various inflammatory diseases. Here, we provide experimental evidence supporting the regulatory role of sphingosine-1-phosphate (S1P) in NLRP3 inflammasome activation in mouse bone-marrow-derived macrophages (BMDMs), along with the S1P receptor subtype involved and underlying regulatory mechanisms. During the priming stage, S1P induced NLRP3 upregulation in BMDMs only when primed with lipopolysaccharide (LPS). In this event, S1P2, but not S1P1, was involved based on the attenuated NLRP3 upregulation with JTE013 (S1P2 antagonist) or S1P2 knockdown. During the activation stage, S1P induced NLRP3 inflammasome activation in LPS-primed BMDMs via caspase-1 activation, interleukin 1β maturation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, and IL-1β secretion. Such NLRP3 inflammasome activation was blocked by either pharmacological inhibition or genetic knockdown of S1P2. NF-κB, PI3K/Akt, and ERK1/2 were identified as effector pathways underlying S1P/S1P2 signaling in the regulation of NLRP3 upregulation in LPS-primed BMDMs. Further, reactive oxygen species (ROS) production was dependent on the S1P/S1P2 signaling axis in these cells, and the ROS generated regulate NLRP3 inflammasome activation, but not NLRP3 priming. Collectively, our findings suggest that S1P promotes NLRP3 upregulation and NLRP3 inflammasome activation in LPS-primed BMDMs via S1P2 and subsequent effector pathways.

scholarly journals Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity

2021 ◽  
Vol 5 (5) ◽  
pp. 1523-1534
Author(s):  
Johan Courjon ◽  
Océane Dufies ◽  
Alexandre Robert ◽  
Laurent Bailly ◽  
Cédric Torre ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Myeloid Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Molecular Pattern ◽  
Nlrp3 Inflammasome Activation ◽  
Healthy Donors ◽  
Activation Potential ◽  
Key Factor ◽  
Pathogen Associated Molecular Pattern

Abstract Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient’s evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.

scholarly journals TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Yahui Zhang ◽  
Baohua Hou ◽  
Peiyu Liang ◽  
Xin Lu ◽  
Yifan Wu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Transient Receptor Potential ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Inflammasome Activation ◽  
Trpv1 Channel ◽  
Nlrp3 Inflammasome Activation

AbstractMultiple sclerosis (MS) is a chronic inflammatory autoimmune disease in the central nervous system (CNS). The NLRP3 inflammasome is considered an important regulator of immunity and inflammation, both of which play a critical role in MS. However, the underlying mechanism of NLRP3 inflammasome activation is not fully understood. Here we identified that the TRPV1 (transient receptor potential vanilloid type 1) channel in microglia, as a Ca2+ influx-regulating channel, played an important role in NLRP3 inflammasome activation. Deletion or pharmacological blockade of TRPV1 inhibited NLRP3 inflammasome activation in microglia in vitro. Further research revealed that TRPV1 channel regulated ATP-induced NLRP3 inflammasome activation through mediating Ca2+ influx and phosphorylation of phosphatase PP2A in microglia. In addition, TRPV1 deletion could alleviate mice experimental autoimmune encephalomyelitis (EAE) and reduce neuroinflammation by inhibiting NLRP3 inflammasome activation. These data suggested that the TRPV1 channel in microglia can regulate NLRP3 inflammasome activation and consequently mediate neuroinflammation. Meanwhile, our study indicated that TRPV1–Ca2+–PP2A pathway may be a novel regulator of NLRP3 inflammasome activation, pointing to TRPV1 as a potential target for CNS inflammatory diseases.

scholarly journals IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Mehboob Ali ◽  
Mehak Gupta ◽  
Abubakar Wani ◽  
Ankita Sharma ◽  
Mohd Abdullaha ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inhibitory Activity ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Synthetic Compound ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α ◽  
Pathological Development ◽  
Inflammasome Activity ◽  
Nlrp3 Activity

Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.

scholarly journals Inhibitory Role of Berberine, an Isoquinoline Alkaloid, on NLRP3 Inflammasome Activation for the Treatment of Inflammatory Diseases

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6238
Author(s):  
Paromita Sarbadhikary ◽  
Blassan P. George ◽  
Heidi Abrahamse
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
In Vivo Studies ◽  
Inflammasome Activation ◽  
Inflammatory Disorders ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.

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 Sinapic Acid Controls Inflammation by Suppressing NLRP3 Inflammasome Activation

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2327
Author(s):  
Eun Hye Lee ◽  
Jin Hak Shin ◽  
Seon Sook Kim ◽  
Su Ryeon Seo
Keyword(s):  
Cinnamic Acid ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Endotoxic Shock ◽  
Sinapic Acid ◽  
Inflammasome Activation ◽  
Cinnamic Acid Derivative ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Anti Inflammatory

A natural phenolic acid compound, sinapic acid (SA), is a cinnamic acid derivative that contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. SA is present in various orally edible natural herbs and cereals and is reported to have antioxidant, antitumor, anti-inflammatory, antibacterial, and neuroprotective activities. Although the anti-inflammatory function of SA has been reported, the effect of SA on the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome has not been explored. In the present study, to elucidate the anti-inflammatory mechanism of SA, we examined whether SA modulates the NLRP3 inflammasome. We found that SA blocked caspase-1 activation and IL-1β secretion by inhibiting NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs). Apoptosis-associated speck-like protein containing CARD (ASC) pyroptosome formation was consistently blocked by SA treatment. SA specifically inhibited NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. In addition, SA had no significant effect on the priming phase of the NLRP3 inflammasome, such as pro-IL-1β and NLRP3 inflammasome expression levels. Moreover, we found that SA attenuated IL-1β secretion in LPS-induced systemic inflammation in mice and reduced lethality from endotoxic shock. Our findings suggest that the natural compound SA has potential therapeutic value for the suppression of NLRP3 inflammasome-associated inflammatory diseases.

NLRP3 inflammasome is involved in uterine activation for labor at term and preterm

Reproduction ◽  
2021 ◽  
Vol 162 (6) ◽  
pp. 449-460
Author(s):  
Zixi Chen ◽  
Yali Shan ◽  
Xingji You ◽  
Hang Gu ◽  
Chen Xu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Pregnant Mice ◽  
Labor Onset

The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases. We sought to investigate the role of NLRP3 inflammasome in uterine activation for labor at term and preterm. We found that NLRP3 inflammasome was activated in the myometrium tissues obtained from the pregnant women undergoing labor at term (TL) compared with those not undergoing labor (TNL) at term. NLRP3 inflammasome was also activated in amnion and chorion-deciduas in TL and preterm labor (PTL) groups. In the mouse model, uterine NLRP3 inflammasome and nuclear factor kappaB (NF-κB) were activated toward term and during labor. Treatment of pregnant mice with lipopolysaccharide (LPS) and RU38486 induced preterm birth (PTB) and also promoted uterine NLRP3 inflammasome and NF-κB activation. Treatment of pregnant mice with NLRP3 inflammasome inhibitor BAY11-7082 and MCC950 delayed the onset of labor and suppressed NLRP3 inflammasome and NF-κB activation in uterus. MCC950 postponed labor onset of the mice with LPS and RU38486 treatment and inhibited NLRP3 inflammasome activation in uterus. Our data provide the evidence that NLRP3 inflammasome is involved in uterine activation for labor onset in term and PTB in humans and mouse model.

scholarly journals Deoxycholic Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Exacerbates DSS-Induced Colitis through Promoting Cathepsin B Release

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Shengnan Zhao ◽  
Zizhen Gong ◽  
Xixi Du ◽  
Chunyan Tian ◽  
Lingyu Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Cathepsin B ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Inflammasome Activation ◽  
High Fat ◽  
Molecular Pattern ◽  
Nlrp3 Inflammasome Activation ◽  
Sphingosine 1 Phosphate

We recently have proved that excessive fecal DCA caused by high-fat diet may serve as an endogenous danger-associated molecular pattern to activate NLRP3 inflammasome and thus contributes to the development of inflammatory bowel disease (IBD). Moreover, the effect of DCA on inflammasome activation is mainly mediated through bile acid receptor sphingosine-1-phosphate receptor 2 (S1PR2); however, the intermediate process remains unclear. Here, we sought to explore the detailed molecular mechanism involved and examine the effect of S1PR2 blockage in a colitis mouse model. In this study, we found that DCA could dose dependently upregulate S1PR2 expression. Meanwhile, DCA-induced NLRP3 inflammasome activation is at least partially achieved through stimulating extracellular regulated protein kinases (ERK) signaling pathway downstream of S1PR2 followed by promoting of lysosomal cathepsin B release. DCA enema significantly aggravated DSS-induced colitis in mice and S1PR2 inhibitor as well as inflammasome inhibition by cathepsin B antagonist substantially reducing the mature IL-1β production and alleviated colonic inflammation superimposed by DCA. Therefore, our findings suggest that S1PR2/ERK1/2/cathepsin B signaling plays a critical role in triggering inflammasome activation by DCA and S1PR2 may represent a new potential therapeutic target for the management of intestinal inflammation in individuals on a high-fat diet.

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.

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