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

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.

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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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Induction of NLRP3 Inflammasome Activation by Heme in Human Endothelial Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4310816 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 31

Author(s):

Judit Erdei ◽

Andrea Tóth ◽

Enikő Balogh ◽

Benard Bogonko Nyakundi ◽

Emese Bányai ◽

...

Keyword(s):

Endothelial Cells ◽

Nlrp3 Inflammasome ◽

Structural Integrity ◽

Umbilical Vein ◽

Critical Role ◽

Protoporphyrin Ix ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Umbilical Vein Endothelial Cells

Hemolytic or hemorrhagic episodes are often associated with inflammation even when infectious agents are absent suggesting that red blood cells (RBCs) release damage-associated molecular patterns (DAMPs). DAMPs activate immune and nonimmune cells through pattern recognition receptors. Heme, released from RBCs, is a DAMP and induces IL-1βproduction through the activation of the nucleotide-binding domain and leucine-rich repeat-containing family and pyrin domain containing 3 (NLRP3) in macrophages; however, other cellular targets of heme-mediated inflammasome activation were not investigated. Because of their location, endothelial cells can be largely exposed to RBC-derived DAMPs; therefore, we investigated whether heme and other hemoglobin- (Hb-) derived species induce NLRP3 inflammasome activation in these cells. We found that heme upregulated NLRP3 expression and induced active IL-1βproduction in human umbilical vein endothelial cells (HUVECs). LPS priming largely amplified the heme-mediated production of IL-1β. Heme administration into C57BL/6 mice induced caspase-1 activation and cleavage of IL-1βwhich was not observed in NLRP3−/−mice. Unfettered production of reactive oxygen species played a critical role in heme-mediated NLRP3 activation. Activation of NLRP3 by heme required structural integrity of the heme molecule, as neither protoporphyrin IX nor iron-induced IL-1βproduction. Neither naive nor oxidized forms of Hb were able to induce IL-1βproduction in HUVECs. Our results identified endothelial cells as a target of heme-mediated NLRP3 activation that can contribute to the inflammation triggered by sterile hemolysis. Thus, understanding the characteristics and cellular counterparts of RBC-derived DAMPs might allow us to identify new therapeutic targets for hemolytic diseases.

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TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia

Cell Death and Disease ◽

10.1038/s41419-021-04450-9 ◽

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.

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

Molecules ◽

10.3390/molecules26206238 ◽

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.

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MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs

International Journal of Molecular Sciences ◽

10.3390/ijms222212413 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12413

Author(s):

Shuang Ge ◽

Wei Yang ◽

Haiqiang Chen ◽

Qi Yuan ◽

Shi Liu ◽

...

Keyword(s):

Liver Fibrosis ◽

Nlrp3 Inflammasome ◽

Inflammatory Cell ◽

Myeloid Cells ◽

Inflammasome Activation ◽

Potential Candidate ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Candidate Target

Chronic liver disease mediated by the activation of hepatic stellate cells (HSCs) leads to liver fibrosis. The signal adaptor MyD88 of Toll-like receptor (TLR) signaling is involved during the progression of liver fibrosis. However, the specific role of MyD88 in myeloid cells in liver fibrosis has not been thoroughly investigated. In this study, we used a carbon tetrachloride (CCl4)-induced mouse fibrosis model in which MyD88 was selectively depleted in myeloid cells. MyD88 deficiency in myeloid cells attenuated liver fibrosis in mice and decreased inflammatory cell infiltration. Furthermore, deficiency of MyD88 in macrophages inhibits the secretion of CXC motif chemokine 2 (CXCL2), which restrains the activation of HSCs characterized by NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation. Moreover, targeting CXCL2 by CXCR2 inhibitors attenuated the activation of HSCs and reduced liver fibrosis. Thus, MyD88 may represent a potential candidate target for the prevention and treatment of liver fibrosis.

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Sinapic Acid Controls Inflammation by Suppressing NLRP3 Inflammasome Activation

Cells ◽

10.3390/cells10092327 ◽

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.

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

Viruses ◽

10.3390/v13040692 ◽

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.

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

Cells ◽

10.3390/cells9081753 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1753 ◽

Cited By ~ 1

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.

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The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3

Frontiers in Immunology ◽

10.3389/fimmu.2021.741839 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tiantian Tang ◽

Ping Li ◽

Xinhui Zhou ◽

Rui Wang ◽

Xiuqin Fan ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Critical Role ◽

Neutrophil Migration ◽

Inflammasome Activation ◽

Regulation Mechanism ◽

Caspase 1 ◽

Nlrp3 Inflammasome Activation

The dysregulation of NLRP3 inflammasome plays a critical role in pathogenesis of various human inflammatory diseases, thus NLRP3 inflammasome activation must be tightly controlled at multiple levels. However, the underlying mechanism regulating NLRP3 inflammasome activation remains unclear. Herein, the effects of Tripartite motif-containing protein 65 (TRIM65) on NLRP3 inflammasome activation and the underlying molecular mechanism were investigated in vitro and in vivo. Inhibition or deletion of Trim65 could significantly strengthen agonist induced NLRP3 inflammasome activation in THP-1 cells and BMDMs, indicated by increased caspase-1 activation and interleukin-1β secretion. However, TRIM65 had no effect on poly (dA: dT)-induced AIM2 inflammasome activation or flagellin-induced IPAF inflammasome activation. Mechanistically, immunoprecipitation assays demonstrated that TRIM65 binds to NACHT domain of NLRP3, promotes lys48- and lys63- linked ubiquitination of NLRP3 and restrains the NEK7-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion. In vivo, three models of inflammatory diseases were used to confirm the suppression role of TRIM65 in NLRP3 inflammasome activation. TRIM65-deficient mice had a higher production of IL-1β induced by lipopolysaccharide in sera, and more IL-1β secretion and neutrophil migration in the ascites, and more severity of joint swelling and associated IL-1β production induced by monosodium urate, suggesting that TRIM65 deficiency was susceptible to inflammation. Therefore, the data elucidate a TRIM65-dependent negative regulation mechanism of NLRP3 inflammasome activation and provide potential therapeutic strategies for the treatment of NLRP3 inflammasome-related diseases.

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Cullin1 represses systematic inflammasome activation by binding and catalyzing NLRP3 ubiquitination

10.1101/289637 ◽

2018 ◽

Author(s):

Pin Wan ◽

Qi Zhang ◽

Weiyong Liu ◽

Yaling Jia ◽

Tianci Wang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Critical Role ◽

Inflammasome Activation ◽

First Line ◽

Physiological Conditions ◽

Nlrp3 Inflammasome Activation ◽

Inflammatory Stimuli ◽

Cellular Stresses

AbstractActivation of the NLRP3 inflammasome is a key process of host immune response, the first line of defense against cellular stresses and pathogen infections. However, excessive inflammasome activation damages the hosts, and thus it must be precisely controlled. The mechanism underlying the repression of systematic inflammasome activation remains largely unknown. This study reveals that CUL1, a key component of the SCF E3 ligase, plays a critical role in regulation of the inflammasome. CUL1 suppresses the inflammasome activation in HEK293T cells, inhibits endogenous NLRP3 in macrophages, and represses inflammatory responses in C57BL/6 mice. Under normal physiological conditions, CUL1 interacts with NLRP3 to disrupt the inflammasome assembly, and catalyzes NLRP3 ubiquitination to repress the inflammasome activation. In response to inflammatory stimuli, CUL1 disassociates from NLRP3 to release the repression of NLRP3 inflammasome activation. This work reveals a distinct mechanism underlying the repression of inflammasome activation under physiological conditions and the induction of inflammasome activation in response to inflammatory stimuli, and thus provides insights into the prevention and treatment of infectious and inflammatory diseases.

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