scholarly journals Role of Lysosomes in Silica-Induced Inflammasome Activation and Inflammation in Absence of MARCO

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Rupa Biswas ◽  
Raymond F. Hamilton ◽  
Andrij Holian
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Scavenger Receptor ◽  
Acid Sphingomyelinase ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
The Difference ◽  
Silica Treatment

MARCO is the predominant scavenger receptor for recognition and binding of silica particles by alveolar macrophages (AM). Previously, it was shown that mice null for MARCO have a greater inflammatory response to silica, but the mechanism was not described. The aim of this study was to determine the relationship between MARCO and NLRP3 inflammasome activity. Silica increased NLRP3 inflammasome activation and release of the proinflammatory cytokine, IL-1β, to a greater extent in MARCO−/−AM compared to wild type (WT) AM. Furthermore, in MARCO−/−AM there was greater cathepsin B release from phagolysosomes, Caspase-1 activation, and acid sphingomyelinase activity compared to WT AM, supporting the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation. The difference in sensitivity to LMP appears to be in cholesterol recycling since increasing cholesterol in AM by treatment with U18666A decreased silica-induced NLRP3 inflammasome activation, and cells lacking MARCO were less able to sequester cholesterol following silica treatment. Taken together, these results demonstrate that MARCO contributes to normal cholesterol uptake in macrophages; therefore, in the absence of MARCO, macrophages are more susceptible to a greater inflammatory response by particulates known to cause NLRP3 inflammasome activation and the effect is due to increased LMP.

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 NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 692
Author(s):  
Carrie-Anne Malinczak ◽  
Charles F. Schuler ◽  
Angela J. Duran ◽  
Andrew J. Rasky ◽  
Mohamed M. Mire ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Severe Disease ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Increased Risk ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

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

2020 ◽  
Author(s):  
Jianjun Jiang ◽  
Jin Yang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Acid Sphingomyelinase ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Abstract Background: The NOD-Like Receptor Protein 3 (NLRP3) inflammasome is a crucial component of an array of inflammatory conditions. It functions by boosting the secretion of pro-inflammatory cytokines: interleukin-1β (IL-1β) and interleukin-18 (IL-18). Previous studies have established the vital role of the acid sphingomyelinase (ASM)/ceramide (Cer) pathway in the functional outcome of cells, with a particular emphasis on the inflammatory processes. This study aimed to explore the effects and associated underlying mechanism of Cer-induced NLRP3 inflammasome activation.Methods: Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells was used as an in vitro inflammatory model. 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 evaluated using ELISA kits. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content.Results: Imipramine, a well-known inhibitor of ASM, significantly inhibited ASM activity and inhibited Cer accumulation, which indicated ASM activation. Besides, it also suppressed the LPS/ATP-induced expression of proteins and mRNA: thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β and IL-18. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced TXNIP/NLRP3 inflammasome activation; however, it did not affect LPS/ATP-induced ASM activation and ceramide production. Further analysis showed that the exogenous C2-Cer treated J774A.1 cells induced the overexpression of TXNIP, NLRP3, caspase-1, IL-1β and IL-18. Besides, TXNIP siRNA or verapamil inhibited C2-Cer-induced TXNIP overexpression and NLRP3 inflammasome activation.Conclusion: This study demonstrated the involvement of the ASM/Cer/TXNIP signaling pathway in NLRP3 inflammasome activation.

scholarly journals Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Chen Dai ◽  
Bin Liu ◽  
Bibo Peng ◽  
Bo Qu ◽  
Jiezhi Lin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Motor Function ◽  
Nlrp3 Inflammasome ◽  
Neuronal Damage ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Cord Injury

Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI.Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage.Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression.Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.

scholarly journals Lysophosphatidic Acid Receptor 5 Contributes to Imiquimod-Induced Psoriasis-Like Lesions through NLRP3 Inflammasome Activation in Macrophages

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1753 ◽  
Author(s):  
Bhakta Prasad Gaire ◽  
Chi-Ho Lee ◽  
Wondong Kim ◽  
Arjun Sapkota ◽  
Do Yup Lee ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Skin Barrier ◽  
Underlying Mechanism ◽  
Inflammasome Activation ◽  
Lpa Receptor ◽  
Nlrp3 Inflammasome Activation ◽  
Injured Skin

The pathogenesis of psoriasis, an immune-mediated chronic skin barrier disease, is not fully understood yet. Here, we identified lysophosphatidic acid (LPA) receptor 5 (LPA5)-mediated signaling as a novel pathogenic factor in psoriasis using an imiquimod-induced psoriasis mouse model. Amounts of most LPA species were markedly elevated in injured skin of psoriasis mice, along with LPA5 upregulation in injured skin. Suppressing the activity of LPA5 with TCLPA5, a selective LPA5 antagonist, improved psoriasis symptoms, including ear thickening, skin erythema, and skin scaling in imiquimod-challenged mice. TCLPA5 administration attenuated dermal infiltration of macrophages that were found as the major cell type for LPA5 upregulation in psoriasis lesions. Notably, TCLPA5 administration attenuated the upregulation of macrophage NLRP3 in injured skin of mice with imiquimod-induced psoriasis. This critical role of LPA5 in macrophage NLRP3 was further addressed using lipopolysaccharide-primed bone marrow-derived macrophages. LPA exposure activated NLRP3 inflammasome in lipopolysaccharide-primed cells, which was evidenced by NLRP3 upregulation, caspase-1 activation, and IL-1β maturation/secretion. This LPA-driven NLRP3 inflammasome activation in lipopolysaccharide-primed cells was significantly attenuated upon LPA5 knockdown. Overall, our findings establish a pathogenic role of LPA5 in psoriasis along with an underlying mechanism, further suggesting LPA5 antagonism as a potential strategy to treat psoriasis.

scholarly journals MCL Plays an Anti-Inflammatory Role inMycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qingwen Zhang ◽  
Xinru Jiang ◽  
Weigang He ◽  
Kailin Wei ◽  
Jinxia Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inhibitory Effect ◽  
Drug Candidate ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation

Mycobacterium tuberculosis(Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1βand TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

scholarly journals Role of ASM/Cer/TXNIP Signaling Module in the NLRP3 Inflammasome Activation

2020 ◽  
Author(s):  
Jianjun Jiang ◽  
Jin Yang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
Acid Sphingomyelinase ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Ceramide Production

Abstract Background: The NLRP3 inflammasome serves as a crucial component in an array of inflammatory conditions by boosting the secretion of pro-inflammatory cytokines: IL-1β and IL-18. Hence, a thorough investigation of the underlying mechanism of NLRP3 activation could ascertain the requisite directionality to the ongoing studies, along with the identification of the novel drug targets for the management of inflammatory diseases. Previous studies have established the vital role of the Acid sphingomyelinase (ASM)/Ceramide (Cer) pathway in the functional outcome of cells, with a particular emphasis on the inflammatory processes. ASM mediates the ceramide production by sphingomyelin hydrolysis. Furthermore, the participation of the ASM/Cer in NLRP3 activation remains ambiguous. Methods: We employed lipopoysaccharide (LPS)/Adenosine Triphosphate (ATP)-induced activation of NLRP3 inflammasome in J774A.1 cells as an in vitro inflammatory model. Results: We observed that imipramine, a well-known inhibitor of ASM, significantly inhibited ASM activity & increased ceramide accumulation, which indicates ASM activation. Besides, it also suppressed the LPS/ATP-induced expression of proteins and mRNA: Thioredoxin interacting protein (TXNIP), NLRP3, Caspase-1, IL-1β and IL-18. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced TXNIP/NLRP3 inflammasome activation; however, it did not affect LPS/ATP-induced ASM activity and ceramide production. Further examination showed that the exogenous C2-ceramide-treated J774A.1 cells induce the overexpression of TXNIP, NLRP3, Caspase-1, IL-1β, and IL-18. Furthermore, verapamil inhibited C2-Ceramide mediated TXNIP overexpression and NLRP3 inflammasome activation. These findings infer that TXNIP overexpression leads to Cer mediated NLRP3 inflammasome activation. Conclusion: Our study validated the crucial role of the ASM/Cer/TXNIP signaling pathway in NLRP3 inflammasome activation.

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

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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