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

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

Reproduction ◽

10.1530/rep-21-0047 ◽

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.

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

Journal of Immunology Research ◽

10.1155/2014/304180 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 18

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.

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Faculty Opinions recommendation of The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735165969.793559816 ◽

2019 ◽

Author(s):

Paras Anand

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Cysteine Cathepsins ◽

Nlrp3 Inflammasome Activation

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The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

Mediators of Inflammation ◽

10.1155/2013/678627 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 48

Author(s):

Elisa Benetti ◽

Fausto Chiazza ◽

Nimesh S. A. Patel ◽

Massimo Collino

Keyword(s):

Chronic Inflammation ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Metabolic Inflammation ◽

Nlrp3 Inflammasome Activation ◽

Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

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Fcγ Receptor IIa (FCGR2A) Polymorphism Is Associated With Severe Respiratory Syncytial Virus Disease in Argentinian Infants

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.607348 ◽

2020 ◽

Vol 10 ◽

Author(s):

María Pía Holgado ◽

Silvina Raiden ◽

Inés Sananez ◽

Vanesa Seery ◽

Leonardo De Lillo ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Virus Disease ◽

Severe Disease ◽

Critical Role ◽

Fcγ Receptor ◽

Factors Associated ◽

Severe Group ◽

Rsv Infection ◽

Syncytial Virus ◽

The Relationship

BackgroundMost patients with respiratory syncytial virus (RSV) infection requiring hospitalization have no risk factors for severe disease. Genetic variation in the receptor for the Fc portion of IgG (FcγR) determines their affinity for IgG subclasses driving innate and adaptive antiviral immunity. We investigated the relationship between FcγRIIa-H131R polymorphism and RSV disease.MethodsBlood samples were collected from 182 infants ≤24-month-old (50 uninfected, 114 RSV-infected with moderate course and 18 suffering severe disease). FcγRIIa-H131R SNP genotypic frequencies (HH, HR, RR) and anti-RSV IgG1, IgG2 and IgG3 levels were studied.ResultsGenotypic frequencies for FcγRIIa-H131R SNP were comparable between uninfected and RSV-infected infants. In contrast, we found a significant higher frequency of HH genotype in severe RSV-infected children compared to moderate patients. Among severe group, HH infants presented more factors associated to severity than HR or RR patients did. Furthermore, compared to moderate RSV-infected infants, severe patients showed higher levels of anti-RSV IgG1 and IgG3.ConclusionsWe found an association between an FcγRIIa (H131) polymorphism and severe RSV disease, which points towards a critical role for interactions between FcγRs and immune complexes in RSV pathogenesis. This genetic factor could also predict the worse outcome and identify those infants at risk during hospitalization.

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Risk of gout flares after vaccination: a prospective case cross-over study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2019-215724 ◽

2019 ◽

Vol 78 (11) ◽

pp. 1601-1604 ◽

Cited By ~ 1

Author(s):

Chio Yokose ◽

Natalie McCormick ◽

Clara Chen ◽

Tuhina Neogi ◽

Christine Chaisson ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Conditional Logistic Regression ◽

Absolute Magnitude ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Increased Risk ◽

Potential Risk Factors ◽

Gout Flare ◽

Gout Flares

ObjectivesThe recombinant zoster vaccine (RZV) containing a strong non-aluminium adjuvant is associated with increased risk of gout flares, presumably via NLRP3 inflammasome activation. We tested the possibility that other vaccines may also be associated with gout flares.MethodsWe conducted an online case-crossover study of patients with gout to examine the association between vaccination and gout flares. We collected information through the Internet on exposures to potential risk factors, including vaccinations, during 2-day hazard periods prior to gout flare and 2-day control periods without a flare. Conditional logistic regression was used to adjust for covariates.ResultsThere were 517 participants with gout (mean age 55 years, 79% male) who experienced gout flares during follow-up. There were 28 vaccinations during 990 hazard periods and 21 vaccinations during 1407 control periods. Vaccination was associated with twofold higher odds of gout flare (adjusted OR 1.99; 95% CI 1.01 to 3.89).ConclusionOur findings suggest vaccines other than RZV are associated with increased odds of gout flares, potentially through a shared pathogenetic mechanism like NLRP3 inflammasome. However, the absolute magnitude of increased odds of gout flares with vaccinations remains small and must be interpreted within the context of the overwhelming benefits of vaccinations.

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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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